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1
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Allington G, Mehta NH, Dennis E, Mekbib KY, Reeves B, Kiziltug E, Chen S, Zhao S, Duy PQ, Saleh M, Ang LC, Fan B, Nelson-Williams C, Moreno-de-Luca A, Haider S, Lifton RP, Alper SL, McGee S, Jin SC, Kahle KT. De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly. Brain 2025; 148:1817-1828. [PMID: 39680505 DOI: 10.1093/brain/awae395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/20/2024] [Accepted: 10/26/2024] [Indexed: 12/18/2024] Open
Abstract
Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is among the most common and least understood paediatric neurosurgical disorders. We have identified, in the largest assembled cerebral ventriculomegaly cohort (2697 parent-proband trios), an exome-wide significant enrichment of protein-altering de novo variants in LDB1 (P = 1.11 × 10-15). Eight unrelated patients with ventriculomegaly, developmental delay and dysmorphic features harboured loss-of-function de novo variants that truncate carboxy-terminal LIM interaction domain of LDB1, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest that LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through its binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging de novo variants in our cohort, with SMARCC1 (P = 5.83 × 10-9) and ARID1B (P = 1.80 × 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest that an LDB1-regulated transcriptional programme is essential for human brain morphogenesis.
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Affiliation(s)
- Garrett Allington
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA
- Department of Neurology, New York Presbyterian Hospital & Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Neel H Mehta
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
| | - Evan Dennis
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
| | - Kedous Y Mekbib
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Benjamin Reeves
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Emre Kiziltug
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Shuang Chen
- School of Pharmacy, University College London, London WC1E 6BT, UK
| | - Shujuan Zhao
- Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Phan Q Duy
- Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Maha Saleh
- Clinical Genetics, Department of Pediatrics, London Health Sciences Centre, London, Ontario N6A 5W9, Canada
| | - Lee C Ang
- Department of Pathology, London Health Sciences Centre and Western University, London, Ontario N6A 5C1, Canada
| | - Baojian Fan
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
| | - Carol Nelson-Williams
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Andrés Moreno-de-Luca
- Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, Ontario K7L 2V7, Canada
| | - Shozeb Haider
- School of Pharmacy, University College London, London WC1E 6BT, UK
| | - Richard P Lifton
- Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA
| | - Seth L Alper
- Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | | | - Sheng Chih Jin
- Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA
- Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Kristopher T Kahle
- Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA
- Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA 02114, USA
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Weekley BH, Ahmed NI, Maze I. Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders. iScience 2025; 28:112092. [PMID: 40160416 PMCID: PMC11951040 DOI: 10.1016/j.isci.2025.112092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
The evolving field of neuroepigenetics provides important insights into the molecular foundations of brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping the epigenetic landscape during neurodevelopment and in disease. Traditional methods to investigate the consequences of chromatin-related mutations provide valuable phenotypic insights but often lack information on the biochemical mechanisms underlying these processes. Recent studies, however, are beginning to elucidate how structural and/or functional aspects of histone, DNA, and RNA post-translational modifications affect transcriptional landscapes and neurological phenotypes. Here, we review the identification of epigenetic regulators from genomic studies of brain disease, as well as mechanistic findings that reveal the intricacies of neuronal chromatin regulation. We then discuss how these mechanistic studies serve as a guideline for future neuroepigenetics investigations. We end by proposing a roadmap to future therapies that exploit these findings by coupling them to recent advances in targeted therapeutics.
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Affiliation(s)
- Benjamin H. Weekley
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Newaz I. Ahmed
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ian Maze
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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van der Sluijs PJ, Safai Pour K, Berends CL, Kruizinga MD, Müller AR, van Eeghen AM, Rodríguez-Girondo M, Juachon MJ, Steenbeek D, Cohen AF, Zuiker RGJA, Santen GWE. Clonazepam repurposing in ARID1B patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development. J Med Genet 2025; 62:210-218. [PMID: 39740803 PMCID: PMC11877031 DOI: 10.1136/jmg-2024-109951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 10/27/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in ARID1B patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects. METHODS This study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, ARID1B patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks). RESULTS In the clonazepam group (n=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed 'no change' after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (n=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient. CONCLUSIONS Our approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in ARID1B patients. TRIAL REGISTRATION NUMBER EUCTR2019-003558-98, ISRCTN11225608.
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Affiliation(s)
| | - Koshar Safai Pour
- Centre for Human Drug Research, Leiden, the Netherlands
- Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Matthijs D Kruizinga
- Centre for Human Drug Research, Leiden, the Netherlands
- Department of Pediatrics, Haga Teaching Hospital, The Hague, the Netherlands
| | - Annelieke R Müller
- Department of Pediatrics, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Advisium, 's Heeren Loo, Amersfoort, the Netherlands
| | - Agnies M van Eeghen
- Department of Pediatrics, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Advisium, 's Heeren Loo, Amersfoort, the Netherlands
| | - Mar Rodríguez-Girondo
- Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Duco Steenbeek
- Department of Rehabilitation Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
- Center of Rehabilitation Medicine, Adelante Zorggroep, Maastricht, the Netherlands
| | - Adam F Cohen
- Centre for Human Drug Research, Leiden, the Netherlands
| | | | - Gijs W E Santen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Chmykhalo VK, Deev RV, Tokarev AT, Polunina YA, Xue L, Shidlovskii YV. SWI/SNF Complex Connects Signaling and Epigenetic State in Cells of Nervous System. Mol Neurobiol 2025; 62:1536-1557. [PMID: 39002058 DOI: 10.1007/s12035-024-04355-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 07/06/2024] [Indexed: 07/15/2024]
Abstract
SWI/SNF protein complexes are evolutionarily conserved epigenetic regulators described in all eukaryotes. In metameric animals, the complexes are involved in all processes occurring in the nervous system, from neurogenesis to higher brain functions. On the one hand, the range of roles is wide because the SWI/SNF complexes act universally by mobilizing the nucleosomes in a chromatin template at multiple loci throughout the genome. On the other hand, the complexes mediate the action of multiple signaling pathways that control most aspects of neural tissue development and function. The issues are discussed to provide insight into the molecular basis of the multifaceted role of SWI/SNFs in cell cycle regulation, DNA repair, activation of immediate-early genes, neurogenesis, and brain and connectome formation. An overview is additionally provided for the molecular basis of nervous system pathologies associated with the SWI/SNF complexes and their contribution to neuroinflammation and neurodegeneration. Finally, we discuss the idea that SWI/SNFs act as an integration platform to connect multiple signaling and genetic programs.
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Affiliation(s)
- Victor K Chmykhalo
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia.
| | - Roman V Deev
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia
| | - Artemiy T Tokarev
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia
| | - Yulia A Polunina
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia
| | - Lei Xue
- School of Life Science and Technology, The First Rehabilitation Hospital of Shanghai, Tongji University, Shanghai, China
| | - Yulii V Shidlovskii
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova St, Moscow, 119334, Russia
- Department of Biology and General Genetics, Sechenov University, Moscow, Russia
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5
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Liu F, Ying J, Yang K, Xiong X, Yang N, Wang S, Zhao W, Zhu H, Yu M, Wu J, Yang J, Wang X, Sun X. Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer. Cell Rep 2024; 43:114916. [PMID: 39475510 DOI: 10.1016/j.celrep.2024.114916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 09/15/2024] [Accepted: 10/09/2024] [Indexed: 12/01/2024] Open
Abstract
ARID1A is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and functions as a critical tumor suppressor in various cancers. In this study, we find that tumor cells with hotspot missense mutations in ARID1A (AT-rich interactive domain-containing protein 1A) exhibit a malignant phenotype. Mechanistically, these mutations facilitate the translocation of ARID1A mutant proteins to the cytoplasm by the nucleocytoplasmic shuttler XPO1 (exportin 1). Subsequently, the E3 ubiquitin ligase STUB1 ubiquitinates the ARID1A mutant protein, marking it for degradation. Knocking down STUB1 or inhibiting XPO1 stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, the chromatin remodeling function, and the normal expression of genes related to the MAPK and anti-apoptotic pathways, thereby decreasing the tumor burden. Our research shows that nuclear-localized mutated ARID1A proteins retain tumor-suppressive function. We identify promising strategies to treat cancers harboring missense mutations in the BAF complex.
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Affiliation(s)
- Fang Liu
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China
| | - Jun Ying
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kai Yang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xinyuan Xiong
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Nan Yang
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shu Wang
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenzhen Zhao
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Huiqin Zhu
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ming Yu
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Wu
- Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China
| | - Jie Yang
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xiaonan Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xuxu Sun
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China.
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Arnold O, Bluemn T, Stelloh C, Rao S, Zhu N. The SWI/SNF subunit ARID1B is important for regenerative ability of hematopoietic stem cells in normal hematopoiesis. PLoS One 2024; 19:e0312616. [PMID: 39446840 PMCID: PMC11500929 DOI: 10.1371/journal.pone.0312616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
The Switch/Sugar non-fermenting (SWI/SNF) nucleosome remodeling complexes are essential for normal hematopoiesis. The Brg1/Brm associated factor (BAF) is a form of mammalian SWI/SNF that is distinguished by the presence of either ARID1A or ARID1B protein. In this study, we used hematopoietic specific Cre mouse models to assess the function of Arid1b in blood development. We found Arid1b loss did not affect steady state hematopoiesis or hematopoietic regeneration. Nonetheless, Arid1b null hematopoietic stem and progenitor cells have reduced ability to reconstitute hematopoietic system compared to wild type cells. Overall, our data indicate Arid1b is largely dispensable for normal hematopoiesis but impairs the regenerative ability of HSPCs.
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Affiliation(s)
- Olivia Arnold
- Versiti Blood Research Institute, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Theresa Bluemn
- Versiti Blood Research Institute, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Cary Stelloh
- Versiti Blood Research Institute, Milwaukee, Wisconsin, United States of America
| | - Sridhar Rao
- Versiti Blood Research Institute, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Department of Pediatrics, Division of Hematology/Oncology/Transplantation, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Nan Zhu
- Versiti Blood Research Institute, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Synthetic Biology Program, J Craig Venter Institute, La Jolla, California, United States of America
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7
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Herzeg A, Borges B, Diafos LN, Gupta N, MacKenzie TC, Sanders SJ. The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review. Prenat Diagn 2024; 44:1354-1366. [PMID: 39218781 DOI: 10.1002/pd.6654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/07/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024]
Abstract
Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20 weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH.
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Affiliation(s)
- Akos Herzeg
- Department of Surgery, University of California, San Francisco, San Francisco, California, USA
- UCSF Center for Maternal-Fetal Precision Medicine, University of California San Francisco, San Francisco, California, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
- Department of Obstetrics and Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA
| | - Beltran Borges
- Department of Surgery, University of California, San Francisco, San Francisco, California, USA
- UCSF Center for Maternal-Fetal Precision Medicine, University of California San Francisco, San Francisco, California, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
| | - Loukas N Diafos
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
- Department of Pediatrics and Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA
| | - Nalin Gupta
- UCSF Center for Maternal-Fetal Precision Medicine, University of California San Francisco, San Francisco, California, USA
- Department of Pediatrics and Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
- Brain Tumor Research Center, University of California, San Francisco, San Francisco, California, USA
| | - Tippi C MacKenzie
- Department of Surgery, University of California, San Francisco, San Francisco, California, USA
- UCSF Center for Maternal-Fetal Precision Medicine, University of California San Francisco, San Francisco, California, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
- Department of Obstetrics and Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA
- Department of Pediatrics and Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA
| | - Stephan J Sanders
- UCSF Center for Maternal-Fetal Precision Medicine, University of California San Francisco, San Francisco, California, USA
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA
- Institute for Developmental and Regenerative Medicine, Oxford University, Oxford, UK
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8
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Malone HA, Roberts CWM. Chromatin remodellers as therapeutic targets. Nat Rev Drug Discov 2024; 23:661-681. [PMID: 39014081 PMCID: PMC11534152 DOI: 10.1038/s41573-024-00978-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2024] [Indexed: 07/18/2024]
Abstract
Large-scale cancer genome sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, more than 20% of cancers harbour mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodelling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodellers, including members of the ISWI, CHD and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodelling complexes has become of great interest, and drugs that target SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets and led to further compounds in clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodelling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurological diseases, vulnerabilities that arise because of these mutations and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.
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Affiliation(s)
- Hayden A Malone
- Division of Molecular Oncology, Department of Oncology, and Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA
- St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Charles W M Roberts
- Division of Molecular Oncology, Department of Oncology, and Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA.
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9
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Mayfield JM, Hitefield NL, Czajewski I, Vanhye L, Holden L, Morava E, van Aalten DMF, Wells L. O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome. J Biol Chem 2024; 300:107599. [PMID: 39059494 PMCID: PMC11381892 DOI: 10.1016/j.jbc.2024.107599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
O-GlcNAc transferase (OGT) is the sole enzyme responsible for the post-translational modification of O-GlcNAc on thousands of target nucleocytoplasmic proteins. To date, nine variants of OGT that segregate with OGT Congenital Disorder of Glycosylation (OGT-CDG) have been reported and characterized. Numerous additional variants have been associated with OGT-CDG, some of which are currently undergoing investigation. This disorder primarily presents with global developmental delay and intellectual disability (ID), alongside other variable neurological features and subtle facial dysmorphisms in patients. Several hypotheses aim to explain the etiology of OGT-CDG, with a prominent hypothesis attributing the pathophysiology of OGT-CDG to mutations segregating with this disorder disrupting the OGT interactome. The OGT interactome consists of thousands of proteins, including substrates as well as interactors that require noncatalytic functions of OGT. A key aim in the field is to identify which interactors and substrates contribute to the primarily neural-specific phenotype of OGT-CDG. In this review, we will discuss the heterogenous phenotypic features of OGT-CDG seen clinically, the variable biochemical effects of mutations associated with OGT-CDG, and the use of animal models to understand this disorder. Furthermore, we will discuss how previously identified OGT interactors causal for ID provide mechanistic targets for investigation that could explain the dysregulated gene expression seen in OGT-CDG models. Identifying shared or unique altered pathways impacted in OGT-CDG patients will provide a better understanding of the disorder as well as potential therapeutic targets.
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Affiliation(s)
- Johnathan M Mayfield
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA
| | - Naomi L Hitefield
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA
| | | | - Lotte Vanhye
- Department of Clinical Genomics and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Laura Holden
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA
| | - Eva Morava
- Department of Clinical Genomics and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Daan M F van Aalten
- School of Life Sciences, University of Dundee, Dundee, UK; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
| | - Lance Wells
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
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10
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Mermet-Meillon F, Mercan S, Bauer-Probst B, Allard C, Bleu M, Calkins K, Knehr J, Altorfer M, Naumann U, Sprouffske K, Barys L, Sesterhenn F, Galli GG. Protein destabilization underlies pathogenic missense mutations in ARID1B. Nat Struct Mol Biol 2024; 31:1018-1022. [PMID: 38347147 PMCID: PMC11257965 DOI: 10.1038/s41594-024-01229-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 01/18/2024] [Indexed: 07/20/2024]
Abstract
ARID1B is a SWI/SNF subunit frequently mutated in human Coffin-Siris syndrome (CSS) and it is necessary for proliferation of ARID1A mutant cancers. While most CSS ARID1B aberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1B is unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin-Siris Syndrome.
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Affiliation(s)
| | - Samuele Mercan
- Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland
| | | | - Cyril Allard
- Disease Area Immunology, Novartis Biomedical Research, Basel, Switzerland
| | - Melusine Bleu
- Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland
| | - Keith Calkins
- Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland
| | - Judith Knehr
- Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland
| | - Marc Altorfer
- Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland
| | - Ulrike Naumann
- Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland
| | | | - Louise Barys
- Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland
| | - Fabian Sesterhenn
- Discovery Sciences, Novartis Biomedical Research, Basel, Switzerland.
| | - Giorgio G Galli
- Disease Area Oncology, Novartis Biomedical Research, Basel, Switzerland.
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11
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Fazel Darbandi S, An JY, Lim K, Page NF, Liang L, Young DM, Ypsilanti AR, State MW, Nord AS, Sanders SJ, Rubenstein JLR. Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes. Cell Rep 2024; 43:114329. [PMID: 38850535 PMCID: PMC11235582 DOI: 10.1016/j.celrep.2024.114329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 09/15/2023] [Accepted: 05/22/2024] [Indexed: 06/10/2024] Open
Abstract
Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.
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Affiliation(s)
- Siavash Fazel Darbandi
- Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Joon-Yong An
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, South Korea; BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, South Korea
| | - Kenneth Lim
- Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nicholas F Page
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Lindsay Liang
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - David M Young
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Athena R Ypsilanti
- Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthew W State
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
| | - Alex S Nord
- Department of Neurobiology, Physiology, and Behavior and Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA
| | - Stephan J Sanders
- Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA; Institute for Developmental and Regenerative Medicine, Old Road Campus, Roosevelt Dr., Headington, Oxford OX3 7TY, UK.
| | - John L R Rubenstein
- Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
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12
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Marshall AH, Boyle DJ, Hanson MA, Nagarajan D, Bibi N, Safa A, Johantges AC, Wester JC. Arid1b haploinsufficiency in cortical inhibitory interneurons causes cell-type-dependent changes in cellular and synaptic development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.07.597984. [PMID: 38895260 PMCID: PMC11185764 DOI: 10.1101/2024.06.07.597984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD. Here, we used transgenic mice to conditionally knockout one copy of the high confidence ASD risk gene Arid1b from the progenitors of parvalbumin-expressing fast-spiking (PV-FS) INs and somatostatin-expressing non-fast-spiking (SST-NFS) INs. In brain slices, we performed paired whole-cell recordings between INs and excitatory projection neurons (PNs) to investigate changes in synaptic physiology. In neonates, we found reduced synaptic input to INs but not PNs, with a concomitant reduction in the frequency of spontaneous network events, which are driven by INs in immature circuits. In mature mice, we found a reduction in the number of PV-FS INs in cortical layers 2/3 and 5. However, changes in PV-FS IN synaptic physiology were cortical layer and PN cell-type dependent. In layer 5, synapses from PV-FS INs to subcortical-projecting PNs were weakened. In contrast, in layer 2/3, synapses to and from PV-FS INs and corticocortical-projecting PNs were strengthened, leading to enhanced feedforward inhibition of input from layer 4. Finally, we found a novel synaptic deficit among SST-NFS INs, in which excitatory synapses from layer 2/3 PNs failed to facilitate. Our data highlight that changes in unitary synaptic dynamics among INs in ASD depend on neuronal cell-type.
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13
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Martins-Costa C, Wiegers A, Pham VA, Sidhaye J, Doleschall B, Novatchkova M, Lendl T, Piber M, Peer A, Möseneder P, Stuempflen M, Chow SYA, Seidl R, Prayer D, Höftberger R, Kasprian G, Ikeuchi Y, Corsini NS, Knoblich JA. ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum. Cell Stem Cell 2024; 31:866-885.e14. [PMID: 38718796 DOI: 10.1016/j.stem.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 02/13/2024] [Accepted: 04/17/2024] [Indexed: 06/09/2024]
Abstract
Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.
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Affiliation(s)
- Catarina Martins-Costa
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, 1030 Vienna, Austria
| | - Andrea Wiegers
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Vincent A Pham
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Jaydeep Sidhaye
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Balint Doleschall
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, 1030 Vienna, Austria
| | - Maria Novatchkova
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Thomas Lendl
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Marielle Piber
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Angela Peer
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Paul Möseneder
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria
| | - Marlene Stuempflen
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Siu Yu A Chow
- Institute of Industrial Science, The University of Tokyo, 153-8505 Tokyo, Japan; Institute for AI and Beyond, The University of Tokyo, 113-0032 Tokyo, Japan
| | - Rainer Seidl
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Daniela Prayer
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Romana Höftberger
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
| | - Gregor Kasprian
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Yoshiho Ikeuchi
- Institute of Industrial Science, The University of Tokyo, 153-8505 Tokyo, Japan; Institute for AI and Beyond, The University of Tokyo, 113-0032 Tokyo, Japan
| | - Nina S Corsini
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria.
| | - Jürgen A Knoblich
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria; Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
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14
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Marshall AH, Hanson MA, Boyle DJ, Nagarajan D, Bibi N, Fitzgerald J, Gaitten E, Kokiko-Cochran ON, Gu B, Wester JC. Arid1b haploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.04.597344. [PMID: 38895205 PMCID: PMC11185765 DOI: 10.1101/2024.06.04.597344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Arid1b is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies of Arid1b from excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disrupting Arid1b expression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed, Arid1b haploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.
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15
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Zhang M, Guo T, Pei F, Feng J, Jing J, Xu J, Yamada T, Ho TV, Du J, Sehgal P, Chai Y. ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling. Nat Commun 2024; 15:4614. [PMID: 38816354 PMCID: PMC11139927 DOI: 10.1038/s41467-024-48285-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.
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Affiliation(s)
- Mingyi Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Tingwei Guo
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Fei Pei
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jian Xu
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Takahiko Yamada
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jiahui Du
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Prerna Sehgal
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA.
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16
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Molinaro G, Bowles JE, Croom K, Gonzalez D, Mirjafary S, Birnbaum SG, Razak KA, Gibson JR, Huber KM. Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α. Cell Rep 2024; 43:114056. [PMID: 38581678 PMCID: PMC11112681 DOI: 10.1016/j.celrep.2024.114056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 01/26/2024] [Accepted: 03/20/2024] [Indexed: 04/08/2024] Open
Abstract
Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.
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Affiliation(s)
- Gemma Molinaro
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jacob E Bowles
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Katilynne Croom
- Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA
| | - Darya Gonzalez
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Saba Mirjafary
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Shari G Birnbaum
- Department of Psychiatry, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Khaleel A Razak
- Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA; Department of Psychology, University of California, Riverside, Riverside, CA, USA
| | - Jay R Gibson
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Kimberly M Huber
- Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
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17
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Kim H, Kim E. Genetic background determines synaptic phenotypes in Arid1b-mutant mice. Front Psychiatry 2024; 14:1341348. [PMID: 38516548 PMCID: PMC10954804 DOI: 10.3389/fpsyt.2023.1341348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 12/22/2023] [Indexed: 03/23/2024] Open
Abstract
ARID1B, a chromatin remodeler, is strongly implicated in autism spectrum disorders (ASD). Two previous studies on Arid1b-mutant mice with the same exon 5 deletion in different genetic backgrounds revealed distinct synaptic phenotypes underlying the behavioral abnormalities: The first paper reported decreased inhibitory synaptic transmission in layer 5 pyramidal neurons in the medial prefrontal cortex (mPFC) region of the heterozygous Arid1b-mutant (Arid1b+/-) brain without changes in excitatory synaptic transmission. In the second paper, in contrast, we did not observe any inhibitory synaptic change in layer 5 mPFC pyramidal neurons, but instead saw decreased excitatory synaptic transmission in layer 2/3 mPFC pyramidal neurons without any inhibitory synaptic change. In the present report, we show that when we changed the genetic background of Arid1b+/- mice from C57BL/6 N to C57BL/6 J, to mimic the mutant mice of the first paper, we observed both the decreased inhibitory synaptic transmission in layer 5 mPFC pyramidal neurons reported in the first paper, and the decreased excitatory synaptic transmission in mPFC layer 2/3 pyramidal neurons reported in the second paper. These results suggest that genetic background can be a key determinant of the inhibitory synaptic phenotype in Arid1b-mutant mice while having minimal effects on the excitatory synaptic phenotype.
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Affiliation(s)
- Hyosang Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Republic of Korea
| | - Eunjoon Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Republic of Korea
- Department of Biological Sciences, Korea Advanced Institute of Science and Technolgoy (KAIST), Daejeon, Republic of Korea
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18
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Davoudi P, Do DN, Colombo S, Rathgeber B, Sargolzaei M, Plastow G, Wang Z, Hu G, Valipour S, Miar Y. Genome-wide association studies for economically important traits in mink using copy number variation. Sci Rep 2024; 14:24. [PMID: 38167844 PMCID: PMC10762091 DOI: 10.1038/s41598-023-50497-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Copy number variations (CNVs) are structural variants consisting of duplications and deletions of DNA segments, which are known to play important roles in the genetics of complex traits in livestock species. However, CNV-based genome-wide association studies (GWAS) have remained unexplored in American mink. Therefore, the purpose of the current study was to investigate the association between CNVs and complex traits in American mink. A CNV-based GWAS was performed with the ParseCNV2 software program using deregressed estimated breeding values of 27 traits as pseudophenotypes, categorized into traits of growth and feed efficiency, reproduction, pelt quality, and Aleutian disease tests. The study identified a total of 10,137 CNVs (6968 duplications and 3169 deletions) using the Affymetrix Mink 70K single nucleotide polymorphism (SNP) array in 2986 American mink. The association analyses identified 250 CNV regions (CNVRs) associated with at least one of the studied traits. These CNVRs overlapped with a total of 320 potential candidate genes, and among them, several genes have been known to be related to the traits such as ARID1B, APPL1, TOX, and GPC5 (growth and feed efficiency traits); GRM1, RNASE10, WNT3, WNT3A, and WNT9B (reproduction traits); MYO10, and LIMS1 (pelt quality traits); and IFNGR2, APEX1, UBE3A, and STX11 (Aleutian disease tests). Overall, the results of the study provide potential candidate genes that may regulate economically important traits and therefore may be used as genetic markers in mink genomic breeding programs.
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Affiliation(s)
- Pourya Davoudi
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Stefanie Colombo
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Bruce Rathgeber
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Mehdi Sargolzaei
- Department of Pathobiology, University of Guelph, Guelph, ON, Canada
- Select Sires Inc., Plain City, OH, USA
| | - Graham Plastow
- Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Zhiquan Wang
- Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Guoyu Hu
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Shafagh Valipour
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada
| | - Younes Miar
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS, Canada.
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19
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Brugmans AK, Walter C, Moreno N, Göbel C, Holdhof D, de Faria FW, Hotfilder M, Jeising D, Frühwald MC, Skryabin BV, Rozhdestvensky TS, Wachsmuth L, Faber C, Dugas M, Varghese J, Schüller U, Albert TK, Kerl K. A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice. Cell Mol Neurobiol 2023; 43:3511-3526. [PMID: 37219662 PMCID: PMC10477118 DOI: 10.1007/s10571-023-01361-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/08/2023] [Indexed: 05/24/2023]
Abstract
The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb11148del/1148del mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes.
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Affiliation(s)
- Aliska K Brugmans
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Carolin Walter
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
- Institute of Medical Informatics, University of Münster, 48149, Münster, Germany
| | - Natalia Moreno
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Carolin Göbel
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Research Institute Children's Cancer Center, 20251, Hamburg, Germany
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Dörthe Holdhof
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Research Institute Children's Cancer Center, 20251, Hamburg, Germany
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Flavia W de Faria
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Marc Hotfilder
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Daniela Jeising
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Michael C Frühwald
- Swabian Children's Cancer Center, Paediatrics and Adolescent Medicine, University Medical Center Augsburg, 86156, Augsburg, Germany
| | - Boris V Skryabin
- Medical Faculty, Core Facility TRAnsgenic Animal and Genetic Engineering Models (TRAM), University of Münster, 48149, Münster, Germany
| | - Timofey S Rozhdestvensky
- Medical Faculty, Core Facility TRAnsgenic Animal and Genetic Engineering Models (TRAM), University of Münster, 48149, Münster, Germany
| | - Lydia Wachsmuth
- Clinic of Radiology, Translational Research Imaging Center (TRIC), University of Münster, 48149, Münster, Germany
| | - Cornelius Faber
- Clinic of Radiology, Translational Research Imaging Center (TRIC), University of Münster, 48149, Münster, Germany
| | - Martin Dugas
- Institute of Medical Informatics, University of Münster, 48149, Münster, Germany
- Institute of Medical Informatics, Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Julian Varghese
- Institute of Medical Informatics, University of Münster, 48149, Münster, Germany
| | - Ulrich Schüller
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Research Institute Children's Cancer Center, 20251, Hamburg, Germany
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Thomas K Albert
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany
| | - Kornelius Kerl
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, 48149, Münster, Germany.
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20
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Tan L, Shi J, Moghadami S, Parasar B, Wright CP, Seo Y, Vallejo K, Cobos I, Duncan L, Chen R, Deisseroth K. Lifelong restructuring of 3D genome architecture in cerebellar granule cells. Science 2023; 381:1112-1119. [PMID: 37676945 PMCID: PMC11059189 DOI: 10.1126/science.adh3253] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 08/03/2023] [Indexed: 09/09/2023]
Abstract
The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.
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Affiliation(s)
- Longzhi Tan
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
- Department of Bioengineering, Stanford University, Stanford, CA, 94305
| | - Jenny Shi
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
- Department of Bioengineering, Stanford University, Stanford, CA, 94305
- Department of Chemistry, Stanford University, Stanford, CA, 94305
| | - Siavash Moghadami
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, 94305
| | - Bibudha Parasar
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
| | - Cydney P. Wright
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
- Department of Biology, Stanford University, Stanford, CA, 94305
| | - Yunji Seo
- Department of Neurobiology, Stanford University, Stanford, CA, 94305
| | - Kristen Vallejo
- Department of Pathology, Stanford University, Stanford, CA, 94305
| | - Inma Cobos
- Department of Pathology, Stanford University, Stanford, CA, 94305
| | - Laramie Duncan
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305
| | - Ritchie Chen
- Department of Bioengineering, Stanford University, Stanford, CA, 94305
| | - Karl Deisseroth
- Department of Bioengineering, Stanford University, Stanford, CA, 94305
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305
- Howard Hughes Medical Institute, Stanford, CA, 94305
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21
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Sandhu A, Kumar A, Rawat K, Gautam V, Sharma A, Saha L. Modernising autism spectrum disorder model engineering and treatment via CRISPR-Cas9: A gene reprogramming approach. World J Clin Cases 2023; 11:3114-3127. [PMID: 37274051 PMCID: PMC10237133 DOI: 10.12998/wjcc.v11.i14.3114] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/13/2023] [Accepted: 04/06/2023] [Indexed: 05/16/2023] Open
Abstract
A neurological abnormality called autism spectrum disorder (ASD) affects how a person perceives and interacts with others, leading to social interaction and communication issues. Limited and recurring behavioural patterns are another feature of the illness. Multiple mutations throughout development are the source of the neurodevelopmental disorder autism. However, a well-established model and perfect treatment for this spectrum disease has not been discovered. The rising era of the clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) system can streamline the complexity underlying the pathogenesis of ASD. The CRISPR-Cas9 system is a powerful genetic engineering tool used to edit the genome at the targeted site in a precise manner. The major hurdle in studying ASD is the lack of appropriate animal models presenting the complex symptoms of ASD. Therefore, CRISPR-Cas9 is being used worldwide to mimic the ASD-like pathology in various systems like in vitro cell lines, in vitro 3D organoid models and in vivo animal models. Apart from being used in establishing ASD models, CRISPR-Cas9 can also be used to treat the complexities of ASD. The aim of this review was to summarize and critically analyse the CRISPR-Cas9-mediated discoveries in the field of ASD.
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Affiliation(s)
- Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
| | - Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 0172, Chandigarh, India
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22
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Doldur-Balli F, Zimmerman AJ, Keenan BT, Shetty ZY, Grant SF, Seiler C, Veatch OJ, Pack AI. Pleiotropic effects of a high confidence Autism Spectrum Disorder gene, arid1b, on zebrafish sleep. Neurobiol Sleep Circadian Rhythms 2023; 14:100096. [PMID: 37287661 PMCID: PMC10241967 DOI: 10.1016/j.nbscr.2023.100096] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 04/29/2023] [Indexed: 06/09/2023] Open
Abstract
Sleep fulfills critical functions in neurodevelopment, such as promoting synaptic plasticity, neuronal wiring, and brain connectivity which are critical phenomena in Autism Spectrum Disorder (ASD) pathophysiology. Sleep disturbance, specifically insomnia, accompanies ASD and is associated with more severe core symptoms (e.g., social impairment). It is possible that focusing on identifying effective ways to treat sleep problems can help alleviate other ASD-related symptoms. A body of evidence indicates shared mechanisms and neurobiological substrates between sleep and ASD and investigation of these may inform therapeutic effects of improving sleep at both behavioral and molecular levels. In this study, we tested if sleep and social behavior were different in a zebrafish model with the arid1b gene mutated compared to controls. This gene was selected for study as expert curations conducted for the Simons Foundation for Autism Research Institute (SFARI) Gene database define it is as a 'high confidence' ASD gene (i.e., clearly implicated) encoding a chromatin remodeling protein. Homozygous arid1b mutants displayed increased arousability and light sleep compared to their heterozygous and wild type counterparts, based on testing a mechano-acoustic stimulus presenting different vibration frequencies of increasing intensity to detect sleep depth. In addition, decreased social preference was observed in arid1b heterozygous and homozygous mutant zebrafish. The behavioral phenotypes reported in our study are in line with findings from mouse models and human studies and demonstrate the utility of zebrafish as a vertebrate model system with high throughput phenotyping in the investigation of changes in sleep in models relevant to ASD. Furthermore, we demonstrate the importance of including assessments of arousal threshold when studying sleep using in vivo models.
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Affiliation(s)
- Fusun Doldur-Balli
- Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Amber J. Zimmerman
- Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Brendan T. Keenan
- Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Zoe Y. Shetty
- Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Struan F.A. Grant
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Divisions of Human Genetics and Endocrinology & Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Christoph Seiler
- Aquatics Core Facility, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Olivia J. Veatch
- Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS, USA
| | - Allan I. Pack
- Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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23
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Ke NY, Zhao TY, Wang WR, Qian YT, Liu C. Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders. World J Stem Cells 2023; 15:235-247. [PMID: 37181007 PMCID: PMC10173807 DOI: 10.4252/wjsc.v15.i4.235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/12/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Different fates of neural stem/progenitor cells (NSPCs) and their progeny are determined by the gene regulatory network, where a chromatin-remodeling complex affects synergy with other regulators. Here, we review recent research progress indicating that the BRG1/BRM-associated factor (BAF) complex plays an important role in NSPCs during neural development and neural developmental disorders. Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation, which can also lead to various diseases in humans. We discussed BAF complex subunits and their main characteristics in NSPCs. With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs, we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs. Considering recent progress in these research areas, we suggest that three approaches should be used in investigations in the near future. Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders. More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.
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Affiliation(s)
- Nai-Yu Ke
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Tian-Yi Zhao
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Wan-Rong Wang
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Yu-Tong Qian
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Chao Liu
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
- Department of Histology and Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China.
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24
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Tan L, Shi J, Moghadami S, Wright CP, Parasar B, Seo Y, Vallejo K, Cobos I, Duncan L, Chen R, Deisseroth K. Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.25.530020. [PMID: 36865235 PMCID: PMC9980173 DOI: 10.1101/2023.02.25.530020] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes (Chd8 or Arid1b). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.
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Affiliation(s)
- Longzhi Tan
- Department of Neurobiology, Stanford University, Stanford, CA
- Department of Bioengineering, Stanford University, Stanford, CA
| | - Jenny Shi
- Department of Neurobiology, Stanford University, Stanford, CA
- Department of Bioengineering, Stanford University, Stanford, CA
- Department of Chemistry, Stanford University, Stanford, CA
| | - Siavash Moghadami
- Department of Neurobiology, Stanford University, Stanford, CA
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA
| | - Cydney P. Wright
- Department of Neurobiology, Stanford University, Stanford, CA
- Department of Biology, Stanford University, Stanford, CA
| | - Bibudha Parasar
- Department of Neurobiology, Stanford University, Stanford, CA
| | - Yunji Seo
- Department of Neurobiology, Stanford University, Stanford, CA
| | | | - Inma Cobos
- Department of Pathology, Stanford University, Stanford, CA
| | - Laramie Duncan
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
| | - Ritchie Chen
- Department of Bioengineering, Stanford University, Stanford, CA
| | - Karl Deisseroth
- Department of Bioengineering, Stanford University, Stanford, CA
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
- Howard Hughes Medical Institute, Stanford, CA
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25
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Xia D, Deng S, Gao C, Li X, Zhang L, Xiao X, Peng X, Zhang J, He Z, Meng Z, Liu Z, Ouyang N, Liang L. ARID2, a rare cause of Coffin-Siris syndrome: A novel microdeletion at 12q12q13.11 causing severe short stature and literature review. Am J Med Genet A 2023; 191:1240-1249. [PMID: 36756859 DOI: 10.1002/ajmg.a.63139] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/11/2023] [Accepted: 01/23/2023] [Indexed: 02/10/2023]
Abstract
Coffin-Siris syndrome (CSS) 6 is caused by heterozygous pathogenic variants in the AT-rich interaction domain 2 (ARID2) gene on 12q12. Currently, only 26 cases with both detailed clinical and genetic information have been documented in the literature. Microdeletions of the entire ARID2 gene are rare. In this study, we report a 5-year-7-month-old Chinese female who underwent whole-exome sequencing to discover that she had a de novo 1.563 Mb heterozygous copy number loss at 12q12q13.11, involving an entire deletion of ARID2. The female had severe short stature with obvious dysmorphic facial features, global developmental delay and hypoplastic fingers and toes. Her growth hormone level was normal, with reduced IGF-1 and increased CA19-9 levels. After a review of the 27 patients with ARID2 deficiency, a significant positive correlation was observed between age and height standard deviation score (SDS) (r = 0.71, p = 0.0002), suggesting a possibility of growth catch-up. This study expands the genetic and phenotypic spectrum of CCS6 and provides a decision-making reference for growth hormone therapy.
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Affiliation(s)
- Dan Xia
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuyun Deng
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chenchen Gao
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojuan Li
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lina Zhang
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqin Xiao
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaofang Peng
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jieming Zhang
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhanwen He
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhe Meng
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zulin Liu
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nengtai Ouyang
- Cellular and Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liyang Liang
- Department of Children's Neuro-endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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26
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Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges. Cells 2023; 12:cells12040538. [PMID: 36831205 PMCID: PMC9954744 DOI: 10.3390/cells12040538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/25/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Neurodevelopmental disorders (NDDs) arise from the disruption of highly coordinated mechanisms underlying brain development, which results in impaired sensory, motor and/or cognitive functions. Although rodent models have offered very relevant insights to the field, the translation of findings to clinics, particularly regarding therapeutic approaches for these diseases, remains challenging. Part of the explanation for this failure may be the genetic differences-some targets not being conserved between species-and, most importantly, the differences in regulation of gene expression. This prompts the use of human-derived models to study NDDS. The generation of human induced pluripotent stem cells (hIPSCs) added a new suitable alternative to overcome species limitations, allowing for the study of human neuronal development while maintaining the genetic background of the donor patient. Several hIPSC models of NDDs already proved their worth by mimicking several pathological phenotypes found in humans. In this review, we highlight the utility of hIPSCs to pave new paths for NDD research and development of new therapeutic tools, summarize the challenges and advances of hIPSC-culture and neuronal differentiation protocols and discuss the best way to take advantage of these models, illustrating this with examples of success for some NDDs.
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27
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Ford TJL, Jeon BT, Lee H, Kim WY. Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability. Front Mol Neurosci 2023; 15:1048713. [PMID: 36743289 PMCID: PMC9892461 DOI: 10.3389/fnmol.2022.1048713] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/05/2022] [Indexed: 01/20/2023] Open
Abstract
Formation of dendritic spine and synapse is an essential final step of brain wiring to establish functional communication in the developing brain. Recent findings have displayed altered dendritic spine and synapse morphogenesis, plasticity, and related molecular mechanisms in animal models and post-mortem human brains of autism spectrum disorders (ASD) and intellectual disability (ID). Many genes and proteins are shown to be associated with spines and synapse development, and therefore neurodevelopmental disorders. In this review, however, particular attention will be given to chromatin modifiers such as AT-Rich Interactive Domain 1B (ARID1B), KAT8 regulatory non-specific lethal (NSL) complex subunit 1 (KANSL1), and WD Repeat Domain 5 (WDR5) which are among strong susceptibility factors for ASD and ID. Emerging evidence highlights the critical status of these chromatin remodeling molecules in dendritic spine morphogenesis and synaptic functions. Molecular and cellular insights of ARID1B, KANSL1, and WDR5 will integrate into our current knowledge in understanding and interpreting the pathogenesis of ASD and ID. Modulation of their activities or levels may be an option for potential therapeutic treatment strategies for these neurodevelopmental conditions.
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28
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Reddy D, Bhattacharya S, Levy M, Zhang Y, Gogol M, Li H, Florens L, Workman JL. Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing. EMBO Rep 2023; 24:e55345. [PMID: 36354291 PMCID: PMC9827562 DOI: 10.15252/embr.202255345] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 10/12/2022] [Accepted: 10/20/2022] [Indexed: 11/12/2022] Open
Abstract
Paraspeckles are subnuclear RNA-protein structures that are implicated in important processes including cellular stress response, differentiation, and cancer progression. However, it is unclear how paraspeckles impart their physiological effect at the molecular level. Through biochemical analyses, we show that paraspeckles interact with the SWI/SNF chromatin-remodeling complex. This is specifically mediated by the direct interaction of the long-non-coding RNA NEAT1 of the paraspeckles with ARID1B of the cBAF-type SWI/SNF complex. Strikingly, ARID1B depletion, in addition to resulting in loss of interaction with the SWI/SNF complex, decreases the binding of paraspeckle proteins to chromatin modifiers, transcription factors, and histones. Functionally, the loss of ARID1B and NEAT1 influences the transcription and the alternative splicing of a common set of genes. Our findings reveal that dynamic granules such as the paraspeckles may leverage the specificity of epigenetic modifiers to impart their regulatory effect, thus providing a molecular basis for their function.
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Affiliation(s)
- Divya Reddy
- Stowers Institute for Medical ResearchKansas CityMOUSA
| | | | | | - Ying Zhang
- Stowers Institute for Medical ResearchKansas CityMOUSA
| | | | - Hua Li
- Stowers Institute for Medical ResearchKansas CityMOUSA
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29
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Celen C, Chuang JC, Shen S, Li L, Maggiore G, Jia Y, Luo X, Moore A, Wang Y, Otto JE, Collings CK, Wang Z, Sun X, Nassour I, Park J, Ghaben A, Wang T, Wang SC, Scherer PE, Kadoch C, Zhu H. Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling. Cell Rep 2022; 41:111581. [DOI: 10.1016/j.celrep.2022.111581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/18/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
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30
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Purushotham SS, Reddy NMN, D'Souza MN, Choudhury NR, Ganguly A, Gopalakrishna N, Muddashetty R, Clement JP. A perspective on molecular signalling dysfunction, its clinical relevance and therapeutics in autism spectrum disorder. Exp Brain Res 2022; 240:2525-2567. [PMID: 36063192 DOI: 10.1007/s00221-022-06448-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/18/2022] [Indexed: 11/29/2022]
Abstract
Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2-3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.
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Affiliation(s)
- Sushmitha S Purushotham
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Neeharika M N Reddy
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Michelle Ninochka D'Souza
- Centre for Brain Research, Indian Institute of Science Campus, CV Raman Avenue, Bangalore, 560 012, India.,The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bangalore, 560064, India
| | - Nilpawan Roy Choudhury
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Anusa Ganguly
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Niharika Gopalakrishna
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Ravi Muddashetty
- Centre for Brain Research, Indian Institute of Science Campus, CV Raman Avenue, Bangalore, 560 012, India.,The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bangalore, 560064, India
| | - James P Clement
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India.
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31
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Kim H, Kim D, Cho Y, Kim K, Roh JD, Kim Y, Yang E, Kim SS, Ahn S, Kim H, Kang H, Bae Y, Kim E. Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming. Nat Commun 2022; 13:5051. [PMID: 36030255 PMCID: PMC9420115 DOI: 10.1038/s41467-022-32748-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 08/12/2022] [Indexed: 11/19/2022] Open
Abstract
Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b+/-) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b+/- mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b+/- mice through transcriptional reprogramming.
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Affiliation(s)
- Hyosang Kim
- Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Doyoun Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea
| | - Yisul Cho
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea
| | - Kyungdeok Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea
| | - Junyeop Daniel Roh
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea
| | - Yangsik Kim
- Graduate School of Biomedical Engineering, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, 34141, Korea
| | - Esther Yang
- Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Seong Soon Kim
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Korea
| | - Sunjoo Ahn
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Korea
| | - Hyun Kim
- Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, 02841, Korea
| | - Hyojin Kang
- Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, 34141, Korea
| | - Yongchul Bae
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, 41940, Korea.
| | - Eunjoon Kim
- Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, 34141, Korea.
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea.
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32
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Dougnon G, Matsui H. Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish. Int J Mol Sci 2022; 23:ijms23147550. [PMID: 35886894 PMCID: PMC9319972 DOI: 10.3390/ijms23147550] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two debilitating neurodevelopmental disorders. The former is associated with social impairments whereas the latter is associated with inattentiveness, hyperactivity, and impulsivity. There is recent evidence that both disorders are somehow related and that genes may play a large role in these disorders. Despite mounting human and animal research, the neurological pathways underlying ASD and ADHD are still not well understood. Scientists investigate neurodevelopmental disorders by using animal models that have high similarities in genetics and behaviours with humans. Mice have been utilized in neuroscience research as an excellent animal model for a long time; however, the zebrafish has attracted much attention recently, with an increasingly large number of studies using this model. In this review, we first discuss ASD and ADHD aetiology from a general point of view to their characteristics and treatments. We also compare mice and zebrafish for their similarities and discuss their advantages and limitations in neuroscience. Finally, we summarize the most recent and existing research on zebrafish and mouse models of ASD and ADHD. We believe that this review will serve as a unique document providing interesting information to date about these models, thus facilitating research on ASD and ADHD.
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33
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Eigenhuis KN, Somsen HB, van den Berg DLC. Transcription Pause and Escape in Neurodevelopmental Disorders. Front Neurosci 2022; 16:846272. [PMID: 35615272 PMCID: PMC9125161 DOI: 10.3389/fnins.2022.846272] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.
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34
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Bluemn T, Schmitz J, Zheng Y, Burns R, Zheng S, DeJong J, Christiansen L, Arnold O, Izaguirre-Carbonell J, Wang D, Deshpande AJ, Zhu N. Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis. Leukemia 2022; 36:946-955. [PMID: 35022500 PMCID: PMC10095935 DOI: 10.1038/s41375-021-01505-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 12/16/2021] [Accepted: 12/23/2021] [Indexed: 11/09/2022]
Abstract
The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.
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Affiliation(s)
- Theresa Bluemn
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jesse Schmitz
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Yongwei Zheng
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Robert Burns
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Shikan Zheng
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Joshua DeJong
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Luke Christiansen
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Olivia Arnold
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Demin Wang
- Blood Research Institute, Versiti, Milwaukee, WI, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Aniruddha J Deshpande
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Nan Zhu
- Blood Research Institute, Versiti, Milwaukee, WI, USA.
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
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35
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Lo T, Kushima I, Aleksic B, Kato H, Nawa Y, Hayashi Y, Otgonbayar G, Kimura H, Arioka Y, Mori D, Ozaki N. Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population. Int Rev Psychiatry 2022; 34:154-167. [PMID: 35699097 DOI: 10.1080/09540261.2022.2072193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case-control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein-protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.
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Affiliation(s)
- Tzuyao Lo
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
| | - Branko Aleksic
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidekazu Kato
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Nawa
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yu Hayashi
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Gantsooj Otgonbayar
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kimura
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuko Arioka
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.,Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Daisuke Mori
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Brain and Mind Research Center, Nagoya University, Nagoya, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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36
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Wilson KD, Porter EG, Garcia BA. Reprogramming of the epigenome in neurodevelopmental disorders. Crit Rev Biochem Mol Biol 2022; 57:73-112. [PMID: 34601997 PMCID: PMC9462920 DOI: 10.1080/10409238.2021.1979457] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/23/2021] [Accepted: 09/08/2021] [Indexed: 02/03/2023]
Abstract
The etiology of neurodevelopmental disorders (NDDs) remains a challenge for researchers. Human brain development is tightly regulated and sensitive to cellular alterations caused by endogenous or exogenous factors. Intriguingly, the surge of clinical sequencing studies has revealed that many of these disorders are monogenic and monoallelic. Notably, chromatin regulation has emerged as highly dysregulated in NDDs, with many syndromes demonstrating phenotypic overlap, such as intellectual disabilities, with one another. Here we discuss epigenetic writers, erasers, readers, remodelers, and even histones mutated in NDD patients, predicted to affect gene regulation. Moreover, this review focuses on disorders associated with mutations in enzymes involved in histone acetylation and methylation, and it highlights syndromes involving chromatin remodeling complexes. Finally, we explore recently discovered histone germline mutations and their pathogenic outcome on neurological function. Epigenetic regulators are mutated at every level of chromatin organization. Throughout this review, we discuss mechanistic investigations, as well as various animal and iPSC models of these disorders and their usefulness in determining pathomechanism and potential therapeutics. Understanding the mechanism of these mutations will illuminate common pathways between disorders. Ultimately, classifying these disorders based on their effects on the epigenome will not only aid in prognosis in patients but will aid in understanding the role of epigenetic machinery throughout neurodevelopment.
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Affiliation(s)
- Khadija D Wilson
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth G Porter
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
| | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
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37
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Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders. Mol Psychiatry 2022; 27:476-489. [PMID: 33686214 PMCID: PMC8423853 DOI: 10.1038/s41380-021-01060-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 02/04/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
ARID1B haploinsufficiency is a frequent cause of intellectual disability (ID) and autism spectrum disorder (ASD), and also leads to emotional disturbances. In this review, we examine past and present clinical and preclinical research into the neurobiological function of ARID1B. The presentation of ARID1B-related disorders (ARID1B-RD) is highly heterogeneous, including varying degrees of ID, ASD, and physical features. Recent research includes the development of suitable clinical readiness assessments for the treatment of ARID1B-RD, as well as similar neurodevelopmental disorders. Recently developed mouse models of Arid1b haploinsufficiency successfully mirror many of the behavioral phenotypes of ASD and ID. These animal models have helped to solidify the molecular mechanisms by which ARID1B regulates brain development and function, including epigenetic regulation of the Pvalb gene and promotion of Wnt/β-catenin signaling in neural progenitors in the ventral telencephalon. Finally, preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some Arid1b haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.
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Abstract
During evolution, the cerebral cortex advances by increasing in surface and the introduction of new cytoarchitectonic areas among which the prefrontal cortex (PFC) is considered to be the substrate of highest cognitive functions. Although neurons of the PFC are generated before birth, the differentiation of its neurons and development of synaptic connections in humans extend to the 3rd decade of life. During this period, synapses as well as neurotransmitter systems including their receptors and transporters, are initially overproduced followed by selective elimination. Advanced methods applied to human and animal models, enable investigation of the cellular mechanisms and role of specific genes, non-coding regulatory elements and signaling molecules in control of prefrontal neuronal production and phenotypic fate, as well as neuronal migration to establish layering of the PFC. Likewise, various genetic approaches in combination with functional assays and immunohistochemical and imaging methods reveal roles of neurotransmitter systems during maturation of the PFC. Disruption, or even a slight slowing of the rate of neuronal production, migration and synaptogenesis by genetic or environmental factors, can induce gross as well as subtle changes that eventually can lead to cognitive impairment. An understanding of the development and evolution of the PFC provide insight into the pathogenesis and treatment of congenital neuropsychiatric diseases as well as idiopathic developmental disorders that cause intellectual disabilities.
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Affiliation(s)
- Sharon M Kolk
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, The Netherlands.
| | - Pasko Rakic
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale University, New Haven, Connecticut, USA.
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39
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Vagus Nerve Stimulation as a Treatment for Fear and Anxiety in Individuals with Autism Spectrum Disorder. JOURNAL OF PSYCHIATRY AND BRAIN SCIENCE 2022; 7. [PMID: 36303861 PMCID: PMC9600938 DOI: 10.20900/jpbs.20220007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Anxiety disorders affect a large percentage of individuals who have an autism spectrum disorder (ASD). In children with ASD, excessive anxiety is also linked to gastrointestinal problems, self-injurious behaviors, and depressive symptoms. Exposure-based cognitive behavioral therapies are effective treatments for anxiety disorders in children with ASD, but high relapse rates indicate the need for additional treatment strategies. This perspective discusses evidence from preclinical research, which indicates that vagus nerve stimulation (VNS) paired with exposure to fear-provoking stimuli and situations could offer benefits as an adjuvant treatment for anxiety disorders that coexist with ASD. Vagus nerve stimulation is approved for use in the treatment of epilepsy, depression, and more recently as an adjuvant in rehabilitative training following stroke. In preclinical models, VNS shows promise in simultaneously enhancing consolidation of extinction memories and reducing anxiety. In this review, we will present potential mechanisms by which VNS could treat fear and anxiety in ASD. We also discuss potential uses of VNS to treat depression and epilepsy in the context of ASD, and noninvasive methods to stimulate the vagus nerve.
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40
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Wang X, Wu H, Sun H, Wang L, Chen L. ARID2, a Rare Cause of Coffin-Siris Syndrome: A Clinical Description of Two Cases. Front Pediatr 2022; 10:911954. [PMID: 35813374 PMCID: PMC9265212 DOI: 10.3389/fped.2022.911954] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 06/01/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Coffin-Siris syndrome (CSS) is a multiple congenital anomaly syndrome characterized by coarse facial features, sparse scalp hair, hypertrichosis, and hypo/aplastic digital nails and phalanges. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCE1, SMARCB1, SMARCA4, SMARCA2, ARID1B, and ARID1A) have been shown to cause CSS. People diagnosed with BAF pathway related diseases are increasing, and ARID2 (NM_152641.4) is the least common of these genes. Mutations in the ARID2 gene is the cause for Coffin-Siris syndrome 6 (CSS6). By now only 16 individuals with CSS have been reported to have pathogenic variants in ARID2. CASE PRESENTATION In this article, we introduced two individuals with clinical features consistent with CSS6 (Coffin-Siris syndrome 6). This article increases the number of reported cases, provides better phenotypic information for this rare syndrome, and allows everyone to better understand the disease. CONCLUSION Our observations indicate that ARID2 mutations could have variable phenotypes, even in patients from the same family.
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Affiliation(s)
- Xiaoyan Wang
- Department of Endocrinology, Children's Hospital of Soochow University, Suzhou, China
| | - Haiying Wu
- Department of Endocrinology, Children's Hospital of Soochow University, Suzhou, China
| | - Hui Sun
- Department of Endocrinology, Children's Hospital of Soochow University, Suzhou, China
| | - Lili Wang
- Department of Endocrinology, Children's Hospital of Soochow University, Suzhou, China
| | - Linqi Chen
- Department of Endocrinology, Children's Hospital of Soochow University, Suzhou, China
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41
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Neural Transcriptomic Analysis of Sex Differences in Autism Spectrum Disorder: Current Insights and Future Directions. Biol Psychiatry 2022; 91:53-60. [PMID: 33551190 DOI: 10.1016/j.biopsych.2020.11.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022]
Abstract
Autism spectrum disorder (ASD) is consistently diagnosed 3 to 5 times more frequently in males than females, a dramatically sex-biased prevalence that suggests the involvement of sex-differential biological factors in modulating risk. The genomic scale of transcriptomic analyses of human brain tissue can provide an unbiased approach for identifying genes and associated functional processes at the intersection of sex-differential and ASD-impacted neurobiology. Several studies characterizing gene expression changes in the ASD brain have been published in recent years with increasing sample size and cellular resolution. These studies report several convergent patterns across data sets and genetically heterogeneous samples in the ASD brain, including elevated expression of gene sets associated with glial and immune function, and reduced expression of gene sets associated with neuronal and synaptic functions. Assessment of neurotypical cortex tissue has reported parallel patterns by sex, with male-elevated expression of overlapping sets of glial/immune-related genes and female-biased expression of neuron-associated genes, suggesting potential roles for these cell types in sex-differential ASD risk mechanisms. However, validating and further exploring these mechanisms is challenged by the available data, as existing studies of ASD brain include a limited number of female ASD donors and focus predominantly on cortex regions not known to show pronounced sex-differential morphology or function. With this review, we summarize convergent findings from several landmark studies of the transcriptome in ASD brain and their relationship to sex-differential gene expression, and we discuss limitations and remaining questions regarding transcriptomic analysis of sex differences in ASD.
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Lu G, Peng Q, Wu L, Zhang J, Ma L. Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin-Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing. BMC Med Genomics 2021; 14:270. [PMID: 34775996 PMCID: PMC8591803 DOI: 10.1186/s12920-021-01119-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/05/2021] [Indexed: 11/25/2022] Open
Abstract
Background Coffin–Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types. Methods Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin–Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs). Results All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487–158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions. Conclusion Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.
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Affiliation(s)
- Guanting Lu
- Department of Pathology, Laboratory of Translational Medicine Research, Deyang Key Laboratory of Tumor Molecular Research, Deyang People's Hospital, No. 173 First Section of TaishanBei Road, Jiangyang District, Deyang, 618000, China.
| | - Qiongling Peng
- Department of Child Healthcare, Shenzhen Baoan Women's and Children's Hospital, Jinan University, 56 Yulyu Road, Baoan District, Shenzhen, 518000, China
| | - Lianying Wu
- Department of Pathology, Laboratory of Translational Medicine Research, Deyang Key Laboratory of Tumor Molecular Research, Deyang People's Hospital, No. 173 First Section of TaishanBei Road, Jiangyang District, Deyang, 618000, China
| | - Jian Zhang
- Department of Pathology, Laboratory of Translational Medicine Research, Deyang Key Laboratory of Tumor Molecular Research, Deyang People's Hospital, No. 173 First Section of TaishanBei Road, Jiangyang District, Deyang, 618000, China
| | - Liya Ma
- Department of Child Healthcare, Shenzhen Baoan Women's and Children's Hospital, Jinan University, 56 Yulyu Road, Baoan District, Shenzhen, 518000, China.
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Kang E, Kang M, Ju Y, Lee SJ, Lee YS, Woo DC, Sung YH, Baek IJ, Shim WH, Son WC, Choi IH, Seo EJ, Yoo HW, Han YM, Lee BH. Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature. J Med Genet 2021; 58:767-777. [PMID: 33051312 DOI: 10.1136/jmedgenet-2020-107111] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/03/2020] [Accepted: 08/26/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. METHODS The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. RESULTS The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. DISCUSSION ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.
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Affiliation(s)
- Eungu Kang
- Department of Pediatrics, Korea University Ansan Hospital, Ansan, Gyeonggi-do, Republic of Korea
| | - Minji Kang
- Asan institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Younghee Ju
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Sang-Joon Lee
- Asan institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong-Seok Lee
- Department of Physiology, Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong-Cheol Woo
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Hoon Sung
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Convergence Medicine, Bio-Medical Institute of Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Jeoung Baek
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Convergence Medicine, Bio-Medical Institute of Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woo Hyun Shim
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woo-Chan Son
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In Hee Choi
- Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea
| | - Eul-Ju Seo
- Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han-Wook Yoo
- Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong-Mahn Han
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Beom Hee Lee
- Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Walsh JJ, Llorach P, Cardozo Pinto DF, Wenderski W, Christoffel DJ, Salgado JS, Heifets BD, Crabtree GR, Malenka RC. Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology 2021; 46:2000-2010. [PMID: 34239048 PMCID: PMC8429585 DOI: 10.1038/s41386-021-01091-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023]
Abstract
Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.
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Affiliation(s)
- Jessica J Walsh
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Pierre Llorach
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Daniel F Cardozo Pinto
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Wendy Wenderski
- Department of Pathology, Stanford Medical School, Stanford, CA, USA
- Department of Genetics, Stanford Medical School, Stanford, CA, USA
- Department of Developmental Biology, Stanford Medical School, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Daniel J Christoffel
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Juliana S Salgado
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Boris D Heifets
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Gerald R Crabtree
- Department of Pathology, Stanford Medical School, Stanford, CA, USA
- Department of Genetics, Stanford Medical School, Stanford, CA, USA
- Department of Developmental Biology, Stanford Medical School, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Robert C Malenka
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
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She Q, Tang E, Peng C, Wang L, Wang D, Tan W. Prenatal genetic testing in 19 fetuses with corpus callosum abnormality. J Clin Lab Anal 2021; 35:e23971. [PMID: 34569664 PMCID: PMC8605137 DOI: 10.1002/jcla.23971] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/02/2021] [Accepted: 07/29/2021] [Indexed: 11/30/2022] Open
Abstract
Background Corpus callosum abnormality (CCA) can lead to epilepsy, moderate severe neurologic or mental retardation. The prognosis of CCA is closely related to genetic etiology. However, copy number variations (CNVs) associated with fetal CCA are still limited and need to be further identified. Only a few scattered cases have been reported to diagnose CCA by whole exome sequencing (WES). Methods Karyotyping analysis, copy number variation sequencing (CNV‐seq), chromosomal microarray analysis (CMA) and WES were parallelly performed for prenatal diagnosis of 19 CCA cases. Results The total detection rate of karyotyping analysis, CMA (or CNV‐seq) and WES were 15.79% (3/19), 21.05% (4/19) and 40.00% (2/5), respectively. Two cases (case 11 and case 15) were diagnosed as aneuploidy (47, XY, + 13 and 47, XX, + 21) by karyotyping analysis and CNV‐seq. Karyotyping analysis revealed an unknown origin fragment (46,XY,add(13)(p11.2)) in case 3, which was further confirmed to originate from p13.3p11.2 of chromosome 17 by CNV‐seq. CMA revealed arr1q43q44 (238923617–246964774) × 1(8.04 Mb) in case 8 with a negative result of chromosome karyotype. WES revealed that 2 of 5 cases with negative results of karyotyping and CNV‐seq or CMA carried pathogenic genes ALDH7A1 and ARID1B. Conclusion Parallel genetic tests showed that CNV‐seq and CMA are able to identify additional, clinically significant cytogenetic information of CCA compared to karyotyping; WES significantly improves the detection rate of genetic etiology of CCA. For the patients with a negative results of CNV‐seq or CMA, further WES test is recommended.
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Affiliation(s)
- Qin She
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
| | - Erfang Tang
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
| | - Cui Peng
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
| | - Li Wang
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
| | - Dandan Wang
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
| | - Weihe Tan
- Prenatal Diagnostic Center, The Six Affiliated Hospital, Guangzhou Medical University or Qingyuan People's Hospital, Qingyuan, China
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Jee YH, Gangat M, Yeliosof O, Temnycky AG, Vanapruks S, Whalen P, Gourgari E, Bleach C, Yu CH, Marshall I, Yanovski JA, Link K, Ten S, Baron J, Radovick S. Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic. Front Genet 2021; 12:697549. [PMID: 34456972 PMCID: PMC8386283 DOI: 10.3389/fgene.2021.697549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/12/2021] [Indexed: 01/31/2023] Open
Abstract
Purpose Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. Methods We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. Results First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). Conclusion Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.
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Affiliation(s)
- Youn Hee Jee
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Mariam Gangat
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Olga Yeliosof
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Adrian G Temnycky
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Selena Vanapruks
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Philip Whalen
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Evgenia Gourgari
- Division of Pediatric Endocrinology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Cortney Bleach
- Division of Pediatric Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, United States
| | - Christine H Yu
- Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, IL, United States
| | - Ian Marshall
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Jack A Yanovski
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Kathleen Link
- Division of Pediatric Endocrinology, Pediatric Subspecialists of Virginia, Fairfax, VA, United States
| | - Svetlana Ten
- Pediatric Endocrinology, Richmond University Medical Center, Staten Island, NY, United States
| | - Jeffrey Baron
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Sally Radovick
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
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D'Souza L, Channakkar AS, Muralidharan B. Chromatin remodelling complexes in cerebral cortex development and neurodevelopmental disorders. Neurochem Int 2021; 147:105055. [PMID: 33964373 PMCID: PMC7611358 DOI: 10.1016/j.neuint.2021.105055] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 04/11/2021] [Accepted: 04/24/2021] [Indexed: 12/19/2022]
Abstract
The diverse number of neurons in the cerebral cortex are generated during development by neural stem cells lining the ventricle, and they continue maturing postnatally. Dynamic chromatin regulation in these neural stem cells is a fundamental determinant of the emerging property of the functional neural network, and the chromatin remodellers are critical determinants of this process. Chromatin remodellers participate in several steps of this process from proliferation, differentiation, migration leading to complex network formation which forms the basis of higher-order functions of cognition and behaviour. Here we review the role of these ATP-dependent chromatin remodellers in cortical development in health and disease and highlight several key mouse mutants of the subunits of the complexes which have revealed how the remodelling mechanisms control the cortical stem cell chromatin landscape for expression of stage-specific transcripts. Consistent with their role in cortical development, several putative risk variants in the subunits of the remodelling complexes have been identified as the underlying causes of several neurodevelopmental disorders. A basic understanding of the detailed molecular mechanism of their action is key to understating how mutations in the same networks lead to disease pathologies and perhaps pave the way for therapeutic development for these complex multifactorial disorders.
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Affiliation(s)
- Leora D'Souza
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India
| | - Asha S Channakkar
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India
| | - Bhavana Muralidharan
- Brain Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore Life Science Cluster, Bangalore, India.
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Yang QQ, Zhai YQ, Wang HF, Cai YC, Ma XY, Yin YQ, Li YD, Zhou GM, Zhang X, Hu G, Zhou JW. Nuclear isoform of FGF13 regulates post-natal neurogenesis in the hippocampus through an epigenomic mechanism. Cell Rep 2021; 35:109127. [PMID: 34010636 DOI: 10.1016/j.celrep.2021.109127] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 02/13/2021] [Accepted: 04/22/2021] [Indexed: 10/21/2022] Open
Abstract
The hippocampus is one of two niches in the mammalian brain with persistent neurogenesis into adulthood. The neurogenic capacity of hippocampal neural stem cells (NSCs) declines with age, but the molecular mechanisms of this process remain unknown. In this study, we find that fibroblast growth factor 13 (FGF13) is essential for the post-natal neurogenesis in mouse hippocampus, and FGF13 deficiency impairs learning and memory. In particular, we find that FGF13A, the nuclear isoform of FGF13, is involved in the maintenance of NSCs and the suppression of neuronal differentiation during post-natal hippocampal development. Furthermore, we find that FGF13A interacts with ARID1B, a unit of Brahma-associated factor chromatin remodeling complex, and suppresses the expression of neuron differentiation-associated genes through chromatin modification. Our results suggest that FGF13A is an important regulator for maintaining the self-renewal and neurogenic capacity of NSCs in post-natal hippocampus, revealing an epigenomic regulatory function of FGFs in neurogenesis.
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Affiliation(s)
- Qiao-Qiao Yang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Ying-Qi Zhai
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Hai-Fang Wang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yu-Chen Cai
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xin-Yue Ma
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yan-Qing Yin
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yan-Dong Li
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Guo-Min Zhou
- Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai 200032, China
| | - Xu Zhang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China
| | - Gang Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
| | - Jia-Wei Zhou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China; Co-innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
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50
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Deogharkar A, Singh SV, Bharambe HS, Paul R, Moiyadi A, Goel A, Shetty P, Sridhar E, Gupta T, Jalali R, Goel N, Gadewal N, Muthukumar S, Shirsat NV. Downregulation of ARID1B, a tumor-suppressor in the WNT subgroup medulloblastoma, activates multiple oncogenic signaling pathways. Hum Mol Genet 2021; 30:1721-1733. [PMID: 33949667 DOI: 10.1093/hmg/ddab134] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/22/2022] Open
Abstract
Medulloblastoma, a common pediatric malignant brain tumor, consists of four distinct molecular subgroups WNT, SHH, Group 3, and Group 4. Exome sequencing of 11 WNT subgroup medulloblastomas from an Indian cohort identified mutations in several chromatin modifier genes, including genes of the mammalian SWI/SNF complex. The genome of WNT subgroup tumors is known to be stable except for monosomy 6. Two tumors, having monosomy 6, carried a loss of function mutation in the ARID1B gene located on chromosome 6. ARID1B expression is also lower in the WNT subgroup tumors compared to other subgroups and normal cerebellar tissues that could result in haploinsufficiency. The shRNA-mediated knockdown of ARID1B expression resulted in a significant increase in the malignant potential of medulloblastoma cells. Transcriptome sequencing identified upregulation of several genes encoding cell adhesion proteins, matrix metalloproteases indicating the epithelial-mesenchymal transition. The ARID1B knockdown also upregulated ERK1/ERK2 and PI3K/AKT signaling with a decrease in the expression of several negative regulators of these pathways. The expression of negative regulators of the WNT signaling like TLE1, MDFI, GPX3, ALX4, DLC1, MEST decreased upon ARID1B knockdown resulting in the activation of the canonical WNT signaling pathway. Synthetic lethality has been reported between SWI-SNF complex mutations and EZH2 inhibition, suggesting EZH2 inhibition as a possible therapeutic modality for WNT subgroup medulloblastomas. Thus, the identification of ARID1B as a tumor suppressor and its downregulation resulting in the activation of multiple signaling pathways opens up opportunities for novel therapeutic modalities for the treatment of WNT subgroup medulloblastoma.
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Affiliation(s)
- Akash Deogharkar
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | - Satishkumar Vishram Singh
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | - Harish Shrikrishna Bharambe
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | - Raikamal Paul
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | | | | | | | | | - Tejpal Gupta
- Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai 400012
| | - Rakesh Jalali
- Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai 400012
| | - Naina Goel
- Department of Pathology, Seth G. S. Medical College, Parel, Mumbai 400012
| | - Nikhil Gadewal
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | - Sahana Muthukumar
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
| | - Neelam Vishwanath Shirsat
- Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210
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