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Kim B, Kostaki A, Matthews SG. Conserved DNA methylation signatures in the prefrontal cortex of female newborn and juvenile guinea pigs following antenatal betamethasone exposure. J Neuroendocrinol 2025; 37:e13499. [PMID: 39924870 PMCID: PMC11975801 DOI: 10.1111/jne.13499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/08/2025] [Accepted: 01/26/2025] [Indexed: 02/11/2025]
Abstract
Antenatal corticosteroids (ACS) improve perinatal survival when there is a risk of preterm birth. Although evidence suggests an increased risk of developing neurobehavioural disorders in exposed offspring, the mechanisms involved remain largely unknown. Here, we investigated the DNA methylation patterns in the prefrontal cortex (PFC) of ACS-exposed guinea pig offspring. We hypothesized that differential methylation will be evident at both newborn and juvenile ages. In two separate cohorts, pregnant guinea pigs were administered a subcutaneous injection of saline or betamethasone (1 mg/kg) on gestational days 50/51 to mimic a single course of ACS. The gDNA was isolated from the PFC of term-born female offspring on postnatal day 1 (PND1, n = 7/group) and PND14 (n = 6-7/group) to identify differentially methylated CpG sites (DMCs) using reduced representative bisulphite sequencing. In the PND1 PFC, 1521 DMCs, annotating 144 genes were identified following ACS. Identified genes are involved in pathways regulating 'developmental cellular process'. In the PND14 PFC, 776 DMCs representing 46 genes were identified and enriched in 'synaptic signalling' pathways. Though no individual DMCs were identified at both PND1 and PND14, differential methylation was consistently observed at the binding sites of transcription factors PLAGL1, TFAP2C, ZNF263 and SP1 at both ages. We have established that ACS exposure leads to altered DNA methylation in the PFC of guinea pig offspring at both newborn and juvenile ages. Notably, a unique methylation signature was consistently observed at four key transcription factor binding sites at both post-natal time points. These changes may predispose the development of altered neurobehavioural phenotypes that have been described in ACS-exposed offspring.
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Affiliation(s)
- Bona Kim
- Department of PhysiologyUniversity of TorontoTorontoOntarioCanada
- Lunenfeld‐Tanenbaum Research InstituteSinai Health SystemTorontoOntarioCanada
| | - Alice Kostaki
- Department of PhysiologyUniversity of TorontoTorontoOntarioCanada
| | - Stephen G. Matthews
- Department of PhysiologyUniversity of TorontoTorontoOntarioCanada
- Lunenfeld‐Tanenbaum Research InstituteSinai Health SystemTorontoOntarioCanada
- Department of Obstetrics & GynecologyUniversity of TorontoTorontoOntarioCanada
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2
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Savchenko RR, Skryabin NA. Transcription factor TCF4: structure, function, and associated diseases. Vavilovskii Zhurnal Genet Selektsii 2024; 28:770-779. [PMID: 39722673 PMCID: PMC11667571 DOI: 10.18699/vjgb-24-85] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/30/2024] [Accepted: 07/23/2024] [Indexed: 12/28/2024] Open
Abstract
Our understanding of human genes - particularly their structure, functions, and regulatory mechanisms - is still limited. The biological role of approximately 20 % of human proteins has not been established yet, and the molecular functions of the known part of the proteome remain poorly understood. This hinders progress in basic and applied biological and medical sciences, especially in treating hereditary diseases, which are caused by mutations and polymorphic variants in individual genes. Therefore, it is crucial to comprehend the mechanisms of protein functioning to address this problem. This further emphasizes the importance of investigating gene functions and molecular pathogenetic pathways associated with single-gene inherited diseases. This review focuses on the TCF4 gene that encodes a transcription factor crucial for nervous system development and functioning. Pathogenic variants in this gene have been linked to a rare genetic disorder, Pitt-Hopkins syndrome, and TCF4 polymorphic variants are associated with several socially significant diseases, including various psychiatric disorders. The pathogenetic mechanisms of these conditions remain unexplored, and the knowledge about TCF4 upregulation and its target genes is limited. TCF4 can be expressed in various isoforms due to the complex structure and regulation of its gene, which complicates the investigation of the protein's functions. Here, we consider the structure and functions of the TCF4 transcription factor. We discuss its potential target genes and the possible loss-of-function pathogenetic mechanisms identified in animal and cellular models of Pitt-Hopkins syndrome. The review also examines the advantages and limitations of potential therapies for Pitt-Hopkins syndrome that are based on TCF4 dosage compensation or altering the activity of TCF4 target genes.
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Affiliation(s)
- R R Savchenko
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - N A Skryabin
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
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Burette AC, Vihma H, Smith AL, Ozarkar SS, Bennett J, Amaral DG, Philpot BD. Transcription factor 4 expression in the developing non-human primate brain: a comparative analysis with the mouse brain. Front Neuroanat 2024; 18:1478689. [PMID: 39502395 PMCID: PMC11534587 DOI: 10.3389/fnana.2024.1478689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 10/04/2024] [Indexed: 11/08/2024] Open
Abstract
Transcription factor 4 (TCF4) has been implicated in a range of neuropsychiatric disorders, including major depressive disorder, bipolar disorder, and schizophrenia. Mutations or deletions in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare neurodevelopmental disorder. A detailed understanding of its spatial expression across the developing brain is necessary for comprehending TCF4 biology and, by extension, to develop effective treatments for TCF4-associated disorders. However, most current knowledge is derived from mouse models, which are invaluable for preclinical studies but may not fully capture the complexities of human neuropsychiatric phenotypes. This study compared TCF4 expression in the developing mouse brain to its regional and cellular expression patterns in normal prenatal, neonatal, and young adult rhesus macaque brains, a species more relevant to human neurodevelopment. While the general developmental expression of TCF4 is largely conserved between macaques and mice, we saw several interspecies differences. Most notably, a distinct layered pattern of TCF4 expression was clear in the developing macaque neocortex but largely absent in the mouse brain. High TCF4 expression was seen in the inner dentate gyrus of adult mice but not in macaques. Conversely, TCF4 expression was higher in the adult macaque striatum compared to the mouse striatum. Further research is needed to show the significance of these interspecies differences. Still, they underscore the importance of integrating rodent and primate studies to comprehensively understand TCF4 function and its implications for human disorders. Moreover, the primate-specific expression patterns of TCF4 will inform genetic and other therapeutic strategies to treat TCF4-associated disorders.
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Affiliation(s)
- Alain C. Burette
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Hanna Vihma
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Audrey L. Smith
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Siddhi S. Ozarkar
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeff Bennett
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis, Davis, CA, United States
- California National Primate Research Center, University of California, Davis, Davis, CA, United States
| | - David G. Amaral
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Davis, Davis, CA, United States
- California National Primate Research Center, University of California, Davis, Davis, CA, United States
| | - Benjamin D. Philpot
- Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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4
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Li C, Qiao L, Ge J, Hu S, Yang H, Hu C, Li T. PLAGL1 overexpression induces cytoplasmic DNA accumulation that triggers cGAS/STING activation. J Cell Mol Med 2024; 28:e70130. [PMID: 39365284 PMCID: PMC11451391 DOI: 10.1111/jcmm.70130] [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: 06/25/2024] [Revised: 08/12/2024] [Accepted: 09/20/2024] [Indexed: 10/05/2024] Open
Abstract
Pancreatic β-cell damage mediated by apoptosis is believed to be a main trigger of type 1 diabetes mellitus (T1DM), which is proposed as an organ-specific autoimmune disease mediated by T cells. Nonetheless, the fundamental origins of T1DM remain uncertain. Here, we illustrate that an increase in PLAGL1 expression induces β-cell apoptosis, as evidenced by mitochondrial membrane impairment and nucleolar degradation. The gene expression levels from cDNA samples were determined using qRT-PCR method. Western blot and Co-immunoprecipitation were applied for protein expression and interactions, respectively. Flow cytometry and TUNEL assay were used to detect pancreatic β cell apoptosis. Female NOD/LtJ mice with recent-onset T1DM has been used in in vivo studies. Glucose-stimulated insulin secretion (GSIS) and glucose tolerance test (GTT) method is used for islet function assessment. Haematoxylin and Eosin (H&E) and Immunohistochemistry (IHC) were performed to evalute histological improvement of islet beta. Subsequent cytoplasmic DNA accumulation triggers DNA senser, the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. STING activation further stimulates downstream IRF3 and NF-kB pathways, thus boost type-I interferon signalling and NF-kB mediated inflammation. These findings elucidate a molecular mechanism linking PLAGL1 induced cell apoptosis to type-I interferon signalling and suggest a potential benefit for targeting cGAS/STING in T1DM treatment.
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Affiliation(s)
- Cheng Li
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Lingyan Qiao
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Juan Ge
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Sicui Hu
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Hongxiu Yang
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Conghui Hu
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
| | - Tang Li
- Department of Pediatric Endocrinologic and Genetic and Metabolic DiseasesQingdao Women and Children's HospitalQingdaoChina
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5
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Papes F, Camargo AP, de Souza JS, Carvalho VMA, Szeto RA, LaMontagne E, Teixeira JR, Avansini SH, Sánchez-Sánchez SM, Nakahara TS, Santo CN, Wu W, Yao H, Araújo BMP, Velho PENF, Haddad GG, Muotri AR. Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content. Nat Commun 2022; 13:2387. [PMID: 35501322 PMCID: PMC9061776 DOI: 10.1038/s41467-022-29942-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 03/31/2022] [Indexed: 01/04/2023] Open
Abstract
Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
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Affiliation(s)
- Fabio Papes
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil.
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Center for Medicinal Chemistry, University of Campinas, Campinas, Sao Paulo, 13083-886, Brazil.
| | - Antonio P Camargo
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Graduate Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Janaina S de Souza
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Vinicius M A Carvalho
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Graduate Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
| | - Ryan A Szeto
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Erin LaMontagne
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - José R Teixeira
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Graduate Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
| | - Simoni H Avansini
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, 13083-887, Brazil
| | - Sandra M Sánchez-Sánchez
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Thiago S Nakahara
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Graduate Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
| | - Carolina N Santo
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
- Center for Medicinal Chemistry, University of Campinas, Campinas, Sao Paulo, 13083-886, Brazil
- Graduate Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
| | - Wei Wu
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Hang Yao
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Barbara M P Araújo
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil
| | - Paulo E N F Velho
- School of Medical Sciences, University of Campinas, Campinas, Sao Paulo, 13083-887, Brazil
| | - Gabriel G Haddad
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Rady Children's Hospital, San Diego, CA, 92123, USA
| | - Alysson R Muotri
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Rady Children's Hospital, San Diego, CA, 92123, USA.
- Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, 92093, USA.
- Center for Academic Research and Training in Anthropogeny (CARTA) and Archealization (ArchC), University of California San Diego, La Jolla, CA, 92093, USA.
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6
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Chan JM, Quintanal-Villalonga Á, Gao VR, Xie Y, Allaj V, Chaudhary O, Masilionis I, Egger J, Chow A, Walle T, Mattar M, Yarlagadda DVK, Wang JL, Uddin F, Offin M, Ciampricotti M, Qeriqi B, Bahr A, de Stanchina E, Bhanot UK, Lai WV, Bott MJ, Jones DR, Ruiz A, Baine MK, Li Y, Rekhtman N, Poirier JT, Nawy T, Sen T, Mazutis L, Hollmann TJ, Pe'er D, Rudin CM. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer. Cancer Cell 2021; 39:1479-1496.e18. [PMID: 34653364 PMCID: PMC8628860 DOI: 10.1016/j.ccell.2021.09.008] [Citation(s) in RCA: 234] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 07/26/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022]
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
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Affiliation(s)
- Joseph M Chan
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA
| | - Álvaro Quintanal-Villalonga
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Vianne Ran Gao
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA; Weill Cornell Medical College, New York, NY 10065, USA
| | - Yubin Xie
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA; Weill Cornell Medical College, New York, NY 10065, USA
| | - Viola Allaj
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ojasvi Chaudhary
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA
| | - Ignas Masilionis
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA
| | - Jacklynn Egger
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Andrew Chow
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas Walle
- Department of Medical Oncology; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Clinical Cooperation Unit Virotherapy; National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Marissa Mattar
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Dig V K Yarlagadda
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA
| | - James L Wang
- Department of Computer Science, Columbia University, New York, NY 10027, USA
| | - Fathema Uddin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael Offin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Metamia Ciampricotti
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Besnik Qeriqi
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Amber Bahr
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Umesh K Bhanot
- Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - W Victoria Lai
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Matthew J Bott
- Thoracic Service, Department of Surgery, Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David R Jones
- Thoracic Service, Department of Surgery, Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Arvin Ruiz
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Marina K Baine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Yanyun Li
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - John T Poirier
- Perlmutter Cancer Center, New York University Langone Health, New York, NY 10065, USA
| | - Tal Nawy
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA
| | - Triparna Sen
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA
| | - Linas Mazutis
- Institute of Biotechnology, Vilnius University, Vilnius, Lithuania
| | - Travis J Hollmann
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Dana Pe'er
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Charles M Rudin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
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7
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Chen HY, Bohlen JF, Maher BJ. Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome. Dev Neurosci 2021; 43:159-167. [PMID: 34134113 DOI: 10.1159/000516666] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/20/2021] [Indexed: 11/19/2022] Open
Abstract
Transcription factor 4 (TCF4, also known as ITF2 or E2-2) is a type I basic helix-loop-helix transcription factor. Autosomal dominant mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare syndromic form of autism spectrum disorder. In this review, we provide an update on the progress regarding our understanding of TCF4 function at the molecular, cellular, physiological, and behavioral levels with a focus on phenotypes and therapeutic interventions. We examine upstream and downstream regulatory networks associated with TCF4 and discuss a range of in vitro and in vivo data with the aim of understanding emerging TCF4-specific mechanisms relevant for disease pathophysiology. In conclusion, we provide comments about exciting future avenues of research that may provide insights into potential new therapeutic targets for PTHS.
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Affiliation(s)
- Huei-Ying Chen
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA,
| | - Joseph F Bohlen
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA
| | - Brady J Maher
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.,Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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8
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Shariq M, Sahasrabuddhe V, Krishna S, Radha S, Nruthyathi, Bellampalli R, Dwivedi A, Cheramangalam R, Reizis B, Hébert J, Ghosh HS. Adult neural stem cells have latent inflammatory potential that is kept suppressed by Tcf4 to facilitate adult neurogenesis. SCIENCE ADVANCES 2021; 7:eabf5606. [PMID: 34020954 PMCID: PMC8139598 DOI: 10.1126/sciadv.abf5606] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/01/2021] [Indexed: 02/04/2025]
Abstract
Inflammation is known to adversely affect adult neurogenesis, wherein the source of inflammation is largely thought to be extraneous to the neurogenic niche. Here, we demonstrate that the adult hippocampal neural progenitors harbor an inflammatory potential that is proactively suppressed by transcription factor 4 (Tcf4). Deletion of Tcf4 in hippocampal nestin-expressing progenitors causes loss of proliferative capacity and acquisition of myeloid inflammatory properties. This transformation abolishes their differentiation potential and causes production of detrimental factors that adversely affect niche cells, causing inflammation in the dentate gyrus. Thus, on one hand, Tcf4 deletion causes abrogation of proliferative progenitors leading to reduction of adult neurogenesis, while on the other, their accompanying inflammatory transformation inflicts inflammation in the niche. Taken together, we provide the first evidence for a latent inflammatory potential of adult hippocampal neural progenitors and identify Tcf4 as a critical regulator that facilitates adult neurogenesis via proactive suppression of this detrimental potential.
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Affiliation(s)
- Mohammad Shariq
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
- The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Vinaya Sahasrabuddhe
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Sreevatsan Krishna
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Swathi Radha
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Nruthyathi
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Ravishankara Bellampalli
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Anukriti Dwivedi
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Rajit Cheramangalam
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India
| | - Boris Reizis
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - Jean Hébert
- Departments of Neuroscience and Genetics, Albert Einstein College of Medicine, New York, NY, USA
| | - Hiyaa S Ghosh
- National Centre for Biological Science, Tata Institute of Fundamental Research (NCBS-TIFR), Bangalore, India.
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9
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Du J, Jing J, Yuan Y, Feng J, Han X, Chen S, Li X, Peng W, Xu J, Ho TV, Jiang X, Chai Y. Arid1a-Plagl1-Hh signaling is indispensable for differentiation-associated cell cycle arrest of tooth root progenitors. Cell Rep 2021; 35:108964. [PMID: 33826897 PMCID: PMC8132592 DOI: 10.1016/j.celrep.2021.108964] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 02/10/2021] [Accepted: 03/17/2021] [Indexed: 12/04/2022] Open
Abstract
Chromatin remodelers often show broad expression patterns in multiple cell types yet can elicit cell-specific effects in development and diseases. Arid1a binds DNA and regulates gene expression during tissue development and homeostasis. However, it is unclear how Arid1a achieves its functional specificity in regulating progenitor cells. Using the tooth root as a model, we show that loss of Arid1a impairs the differentiation-associated cell cycle arrest of tooth root progenitors through Hedgehog (Hh) signaling regulation, leading to shortened roots. Our data suggest that Plagl1, as a co-factor, endows Arid1a with its cell-type/spatial functional specificity. Furthermore, we show that loss of Arid1a leads to increased expression of Arid1b, which is also indispensable for odontoblast differentiation but is not involved in regulation of Hh signaling. This study expands our knowledge of the intricate interactions among chromatin remodelers, transcription factors, and signaling molecules during progenitor cell fate determination and lineage commitment.
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Affiliation(s)
- Jiahui Du
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Yuan Yuan
- 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
| | - Xia Han
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Shuo Chen
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Xiang Li
- Department of Physics, George Washington University, Washington, DC 20052, USA
| | - Weiqun Peng
- Department of Physics, George Washington University, Washington, DC 20052, USA
| | - Jian Xu
- 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
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
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10
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Teixeira JR, Szeto RA, Carvalho VMA, Muotri AR, Papes F. Transcription factor 4 and its association with psychiatric disorders. Transl Psychiatry 2021; 11:19. [PMID: 33414364 PMCID: PMC7791034 DOI: 10.1038/s41398-020-01138-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/28/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023] Open
Abstract
The human transcription factor 4 gene (TCF4) encodes a helix-loop-helix transcription factor widely expressed throughout the body and during neural development. Mutations in TCF4 cause a devastating autism spectrum disorder known as Pitt-Hopkins syndrome, characterized by a range of aberrant phenotypes including severe intellectual disability, absence of speech, delayed cognitive and motor development, and dysmorphic features. Moreover, polymorphisms in TCF4 have been associated with schizophrenia and other psychiatric and neurological conditions. Details about how TCF4 genetic variants are linked to these diseases and the role of TCF4 during neural development are only now beginning to emerge. Here, we provide a comprehensive review of the functions of TCF4 and its protein products at both the cellular and organismic levels, as well as a description of pathophysiological mechanisms associated with this gene.
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Affiliation(s)
- José R. Teixeira
- grid.411087.b0000 0001 0723 2494Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo Brazil
| | - Ryan A. Szeto
- grid.266100.30000 0001 2107 4242Department of Pediatrics/Rady Children’s Hospital, School of Medicine, University of California San Diego, La Jolla, CA USA
| | - Vinicius M. A. Carvalho
- grid.411087.b0000 0001 0723 2494Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo Brazil ,grid.266100.30000 0001 2107 4242Department of Pediatrics/Rady Children’s Hospital, School of Medicine, University of California San Diego, La Jolla, CA USA
| | - Alysson R. Muotri
- grid.266100.30000 0001 2107 4242Department of Pediatrics/Rady Children’s Hospital, School of Medicine, University of California San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA USA ,grid.266100.30000 0001 2107 4242Center for Academic Research and Training in Anthropogeny (CARTA), University of California San Diego, La Jolla, CA USA
| | - Fabio Papes
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil. .,Department of Pediatrics/Rady Children's Hospital, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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11
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He J, Huang Y, Liu J, Ge L, Tang X, Lu M, Hu Z. Hypoxic conditioned promotes the proliferation of human olfactory mucosa mesenchymal stem cells and relevant lncRNA and mRNA analysis. Life Sci 2020; 265:118861. [PMID: 33301811 DOI: 10.1016/j.lfs.2020.118861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 02/07/2023]
Abstract
AIMS LncRNAs are involved in many biological processes, and hypoxia contributed to the alterations of lncRNAs. Hypoxic preconditioned olfactory mucosa mesenchymal stem cells (OM-MSCs) exerted stronger anti-apoptotic ability in models of disease, but the molecules that controlled different biological characteristics of human OM-MSCs between hypoxic and normoxic conditions were unclear. The present study was aimed to explore the molecules that controlled different biological characteristics of human OM-MSCs between hypoxic and normoxic conditions. MAIN METHODS LncRNAs and mRNAs expression profiles of human OM-MSCs between hypoxic (3%) and normoxic conditions were analyzed by Next-Generation Sequencing (NGS) analysis, bioinformatics analysis on these data were further performed. Moreover, loss-of function assay was conducted to investigate the impact of hypoxic condition on the proliferation and apoptosis of OM-MSCs. KEY FINDINGS Through the comparative analysis and bioinformatics analysis, a total of 1741 lncRNAs and 1603 mRNAs were significant differentially expressed in the hypoxia group compared with normoxia group. Enrichment analysis revealed that differentially expressed genes of human OM-MSCs mainly participated in cell cycle regulation, secretin of cytokines and so on. Meanwhile, hypoxic condition significantly promoted proliferation and inhibited apoptosis of human OM-MSCs, following loss-of-function assays confirmed that lncRNA DARS-AS1 were involved in this regulatory process by hypoxic condition. Further prediction of targeted genes and the construction of lncRNA-miRNA-mRNA interaction network enriched the significance regarding the mechanism of DARS-AS1. SIGNIFICANCE Altogether, these findings provided a new perspective for understanding the molecules expression patterns in hypoxia that contributed to corresponding phenotype alterations of OM-MSCs.
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Affiliation(s)
- Jialin He
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China
| | - Yan Huang
- National Health Commission Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, Hunan, PR China; Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, PR China; Hunan Provincial Key Laboratory of Neurorestoratology, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, PR China
| | - Jianyang Liu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China
| | - Lite Ge
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China
| | - Xiangqi Tang
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China
| | - Ming Lu
- Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, PR China; Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, PR China; Hunan Provincial Key Laboratory of Neurorestoratology, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, PR China.
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China.
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12
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Braun K, Häberle BM, Wittmann MT, Lie DC. Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice. BMC Neurosci 2020; 21:50. [PMID: 33228529 PMCID: PMC7684915 DOI: 10.1186/s12868-020-00602-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life. Results We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice. Conclusion The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.
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Affiliation(s)
- Katharina Braun
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Benjamin M Häberle
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Marie-Theres Wittmann
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
| | - D Chichung Lie
- Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
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13
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Xu B, Mulvey B, Salie M, Yang X, Matsui Y, Nityanandam A, Fan Y, Peng JC. UTX/KDM6A suppresses AP-1 and a gliogenesis program during neural differentiation of human pluripotent stem cells. Epigenetics Chromatin 2020; 13:38. [PMID: 32977832 PMCID: PMC7519529 DOI: 10.1186/s13072-020-00359-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 09/15/2020] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND UTX/KDM6A is known to interact and influence multiple different chromatin modifiers to promote an open chromatin environment to facilitate gene activation, but its molecular activities in developmental gene regulation remain unclear. RESULTS We report that in human neural stem cells, UTX binding correlates with both promotion and suppression of gene expression. These activities enable UTX to modulate neural stem cell self-renewal, promote neurogenesis, and suppress gliogenesis. In neural stem cells, UTX has a less influence over histone H3 lysine 27 and lysine 4 methylation but more predominantly affects histone H3 lysine 27 acetylation and chromatin accessibility. Furthermore, UTX suppresses components of AP-1 and, in turn, a gliogenesis program. CONCLUSIONS Our findings revealed that UTX coordinates dualistic gene regulation to govern neural stem cell properties and neurogenesis-gliogenesis switch.
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Affiliation(s)
- Beisi Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Brett Mulvey
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Muneeb Salie
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Xiaoyang Yang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Yurika Matsui
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Anjana Nityanandam
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Jamy C Peng
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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14
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Gene expression profiling identifies the role of Zac1 in cervical cancer metastasis. Sci Rep 2020; 10:11837. [PMID: 32678267 PMCID: PMC7367306 DOI: 10.1038/s41598-020-68835-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 05/06/2020] [Indexed: 12/22/2022] Open
Abstract
The zinc-finger protein which regulates apoptosis and cell cycle arrest 1 (Zac1), encoded by Plagl1 gene, is a seven-zinc-finger containing transcription factor belonging to the imprinted genome and is expressed in diverse types of embryonic and adult human tissues. Zac1 is postulated to be a tumor suppressor by inducing cell cycle arrest and apoptosis through interacting and modulating transcriptional activity of p53 as it was named. Correspondingly, the reduction or loss of Zac1 expression is associated with the incidence and progression of several human tumors, including cervical cancer, breast cancer, ovarian cancer, pituitary tumors, and basal cell carcinoma, implying the rationality of utilizing Zac1 expression as novel a biomarker for the evaluation of cervical cancer prognosis. However, to date, it has not been elucidated whether Zac1 expression is related to the prognosis of patients in clinical cervical cancer tumor samples. To address the questions outlined above, we report here a comprehensive investigation of Zac1 expression in biopsies of clinical cervical carcinoma. By analyzing Zac1 expression in various gene expression profiling of cervical cancer databases, we show the association between high Zac1 expression and poor prognosis of cervical cancer. Functional enrichment analysis showed that high Zac1 expression was associated with epithelial-mesenchymal transition (EMT), which was further observed in clinical characteristics and metastatic carcinoma samples using immunohistochemical staining. Correspondingly, hypomethylation of CpG island on Zac1 promoter was observed in samples with high Zac1 expression in cervical carcinoma. Finally, overexpression of Zac1 in a variety of cervical cancer cell lines increase their mesenchymal biomarker expression and migration, strengthening the correlation between cervical cancers with high Zac1 expression and metastasis in clinical. In summary, this research firstly revealed that identifying Zac1 expression or the methylation status of CpG site on Zac1 promoter may provide us with novel indicators for the evaluation of cervical cancer metastasis.
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15
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Hwang JS, Yoon CK, Hyon JY, Chung TY, Shin YJ. Transcription Factor 4 Regulates the Regeneration of Corneal Endothelial Cells. Invest Ophthalmol Vis Sci 2020; 61:21. [PMID: 32301972 PMCID: PMC7401711 DOI: 10.1167/iovs.61.4.21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose Human corneal endothelial cells (hCECs) have limited regenerative capacity in vivo. Reduced hCEC density results in bullous keratopathy requiring corneal transplantation. This study reveals the role of transcription factor 4 (TCF4) in hCEC diseases and suggests that TCF4 may be a molecular target for hCEC regeneration. Methods Cell shape, cell proliferation rates, and proliferation-associated proteins were evaluated in normal or senescent hCECs. TCF4 was blocked by siRNA (si-TCF4) or activated using clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 activation systems (pl-TCF4). The corneal endothelium of six-week-old Sprague-Dawley (SD) rats was transfected by electroporation followed by cryoinjury. Results Cell proliferation rates and TCF4 levels were reduced in senescent cells. TCF4 CRISPR activation enhanced corneal endothelial wound healing. TCF4 regulated mitochondrial functions including mitochondrial membrane potential, mitochondrial superoxide levels, and energy production. The percentage of cells in the S-phase was reduced with si-TCF4 and increased with pl-TCF4. Cell proliferation and cell cycle-associated proteins were regulated by TCF4. Autophagy was induced by si-TCF4. In vivo transfection of CRISPR/dCas9 activation systems (a-TCF4) induced regeneration of corneal endothelium. Conclusions Corneal endothelial diseases are associated with TCF4 reduction; TCF4 may be a potential target for hCEC diseases. Gene therapy using TCF4 CRISPR/dCas9 may be an effective treatment for hCEC diseases.
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16
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Li M, Santpere G, Kawasawa YI, Evgrafov OV, Gulden FO, Pochareddy S, Sunkin SM, Li Z, Shin Y, Zhu Y, Sousa AMM, Werling DM, Kitchen RR, Kang HJ, Pletikos M, Choi J, Muchnik S, Xu X, Wang D, Lorente-Galdos B, Liu S, Giusti-Rodríguez P, Won H, de Leeuw CA, Pardiñas AF, Hu M, Jin F, Li Y, Owen MJ, O’Donovan MC, Walters JTR, Posthuma D, Reimers MA, Levitt P, Weinberger DR, Hyde TM, Kleinman JE, Geschwind DH, Hawrylycz MJ, State MW, Sanders SJ, Sullivan PF, Gerstein MB, Lein ES, Knowles JA, Sestan N. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science 2018; 362:eaat7615. [PMID: 30545854 PMCID: PMC6413317 DOI: 10.1126/science.aat7615] [Citation(s) in RCA: 495] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 11/15/2018] [Indexed: 12/14/2022]
Abstract
To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
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Affiliation(s)
- Mingfeng Li
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Gabriel Santpere
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Yuka Imamura Kawasawa
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- Departments of Pharmacology and Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Oleg V. Evgrafov
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn NY, USA
| | - Forrest O. Gulden
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Sirisha Pochareddy
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | | | - Zhen Li
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Yurae Shin
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- National Research Foundation of Korea, Daejeon, South Korea
| | - Ying Zhu
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - André M. M. Sousa
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Donna M. Werling
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | - Robert R. Kitchen
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
| | - Hyo Jung Kang
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- Department of Life Science, Chung-Ang University, Seoul, Korea
| | - Mihovil Pletikos
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- Department of Anatomy & Neurobiology, Boston University School of Medicine, MA, USA
| | - Jinmyung Choi
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Sydney Muchnik
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Xuming Xu
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Daifeng Wang
- Department of Biomedical Informatics Stony Brook University, NY, USA
| | - Belen Lorente-Galdos
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Shuang Liu
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
| | | | - Hyejung Won
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Christiaan A. de Leeuw
- Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, Netherlands
| | - Antonio F. Pardiñas
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | | | | | | | - Ming Hu
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Fulai Jin
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, OH, USA
| | - Yun Li
- Department of Genetics and Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
| | - Michael J. Owen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Michael C. O’Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - James T. R. Walters
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Danielle Posthuma
- Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, Netherlands
| | - Mark A. Reimers
- Neuroscience Program and Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Pat Levitt
- Department of Pediatrics, Institute for the Developing Mind Keck School of Medicine of USC, Los Angeles, CA, USA
- Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Daniel R. Weinberger
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Thomas M. Hyde
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Joel E. Kleinman
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Daniel H. Geschwind
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Center for Autism Research and Treatment, Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Matthew W. State
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | - Stephan J. Sanders
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | | | - Mark B. Gerstein
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
- Department of Computer Science, Yale University, New Haven, CT, USA
- Department of Statistics & Data Science, Yale University, New Haven, CT, USA
| | - Ed S. Lein
- Allen Institute for Brain Science, Seattle, WA, USA
| | - James A. Knowles
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn NY, USA
| | - Nenad Sestan
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT, USA
- Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine, New Haven, CT, USA
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17
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Loera-Valencia R, Piras A, Ismail MAM, Manchanda S, Eyjolfsdottir H, Saido TC, Johansson J, Eriksdotter M, Winblad B, Nilsson P. Targeting Alzheimer's disease with gene and cell therapies. J Intern Med 2018; 284:2-36. [PMID: 29582495 DOI: 10.1111/joim.12759] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) causes dementia in both young and old people affecting more than 40 million people worldwide. The two neuropathological hallmarks of the disease, amyloid beta (Aβ) plaques and neurofibrillary tangles consisting of protein tau are considered the major contributors to the disease. However, a more complete picture reveals significant neurodegeneration and decreased cell survival, neuroinflammation, changes in protein and energy homeostasis and alterations in lipid and cholesterol metabolism. In addition, gene and cell therapies for severe neurodegenerative disorders have recently improved technically in terms of safety and efficiency and have translated to the clinic showing encouraging results. Here, we review broadly current data within the field for potential targets that could modify AD through gene and cell therapy strategies. We envision that not only Aβ will be targeted in a disease-modifying treatment strategy but rather that a combination of treatments, possibly at different intervention times may prove beneficial in curing this devastating disease. These include decreased tau pathology, neuronal growth factors to support neurons and modulation of neuroinflammation for an appropriate immune response. Furthermore, cell based therapies may represent potential strategies in the future.
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Affiliation(s)
- R Loera-Valencia
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden
| | - A Piras
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden
| | - M A M Ismail
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden.,Theme Neuro, Diseases of the Nervous System Patient Flow, Karolinska University Hospital, Huddinge, Sweden
| | - S Manchanda
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden
| | - H Eyjolfsdottir
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - T C Saido
- RIKEN Brain Science Institute, Wako, Saitama, Japan
| | - J Johansson
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden
| | - M Eriksdotter
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - B Winblad
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - P Nilsson
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden
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18
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Omrani MR, Yaqubi M, Mohammadnia A. Transcription Factors in Regulatory and Protein Subnetworks during Generation of Neural Stem Cells and Neurons from Direct Reprogramming of Non-fibroblastic Cell Sources. Neuroscience 2018; 380:63-77. [PMID: 29653196 DOI: 10.1016/j.neuroscience.2018.03.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 12/31/2022]
Abstract
Direct reprogramming of non-fibroblastic cells to the neuronal cell types including induced neurons (iNs) and induced neural stem cells (iNSCs) has provided an alternative approach for the direct reprogramming of fibroblasts to those cells. However, to increase the efficiency of the reprogramming process the underlying mechanisms should be clarified. In the current study, we analyzed the gene expression profiles of five different cellular conversions to understand the most significant molecular mechanisms and transcription factors (TFs) underlying each conversion. For each conversion, we found the list of differentially expressed genes (DEGs) and the list of differentially expressed TFs (DE-TFs) which regulate expression of DEGs. Moreover, we constructed gene regulatory networks based on the TF-binding sites' data and found the most central regulators and the most active part of the networks. Furthermore, protein complexes were identified from constructed protein-protein interaction networks for DE-TFs. Finally, we proposed a list of main regulators for each conversion; for example, in the direct conversion of epithelial-like cells (ECs) to iNSCs, combination of centrality with active modules or protein complex analyses highlighted the role of POU3F2, BACH1, AR, PBX1, SOX2 and NANOG genes in this conversion. To the best of our knowledge, this study is the first one that analyzed the direct conversion of non-fibroblastic cells toward iNs and iNSCs and we believe that the expression manipulation of identified genes may increase efficiency of these processes.
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Affiliation(s)
- Mohammad Reza Omrani
- National Institute of Genetics Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Moein Yaqubi
- Department of Psychiatry, Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
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19
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Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases. Int J Mol Sci 2018; 19:ijms19041055. [PMID: 29614816 PMCID: PMC5979523 DOI: 10.3390/ijms19041055] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 03/31/2018] [Accepted: 03/31/2018] [Indexed: 12/28/2022] Open
Abstract
The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases.
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20
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Jung M, Häberle BM, Tschaikowsky T, Wittmann MT, Balta EA, Stadler VC, Zweier C, Dörfler A, Gloeckner CJ, Lie DC. Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons. Mol Autism 2018; 9:20. [PMID: 29588831 PMCID: PMC5863811 DOI: 10.1186/s13229-018-0200-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 02/20/2018] [Indexed: 12/21/2022] Open
Abstract
Background Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.
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Affiliation(s)
- Matthias Jung
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Benjamin M Häberle
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tristan Tschaikowsky
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Marie-Theres Wittmann
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.,2Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elli-Anna Balta
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Vivien-Charlott Stadler
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christiane Zweier
- 2Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Arnd Dörfler
- Department of Neuroradiology, University Clinic Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christian Johannes Gloeckner
- 4German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.,5Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, 72076 Tübingen, Germany
| | - D Chichung Lie
- 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
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21
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Zacharias WJ, Frank DB, Zepp JA, Morley MP, Alkhaleel FA, Kong J, Zhou S, Cantu E, Morrisey EE. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 2018; 555:251-255. [PMID: 29489752 PMCID: PMC6020060 DOI: 10.1038/nature25786] [Citation(s) in RCA: 496] [Impact Index Per Article: 70.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 01/24/2018] [Indexed: 12/11/2022]
Abstract
Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.
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Affiliation(s)
- William J Zacharias
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - David B Frank
- Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.,Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Jarod A Zepp
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Michael P Morley
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Farrah A Alkhaleel
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Jun Kong
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Su Zhou
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Edward Cantu
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Edward E Morrisey
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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22
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Yang Q, Li Y, Zhang X, Chen D. Zac1/GPR39 phosphorylating CaMK-II contributes to the distinct roles of Pax3 and Pax7 in myogenic progression. Biochim Biophys Acta Mol Basis Dis 2018; 1864:407-419. [DOI: 10.1016/j.bbadis.2017.10.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 09/15/2017] [Accepted: 10/22/2017] [Indexed: 12/12/2022]
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Lozano-Ureña A, Montalbán-Loro R, Ferguson-Smith AC, Ferrón SR. Genomic Imprinting and the Regulation of Postnatal Neurogenesis. Brain Plast 2017; 3:89-98. [PMID: 29765862 PMCID: PMC5928554 DOI: 10.3233/bpl-160041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Most genes required for mammalian development are expressed from both maternally and paternally inherited chromosomal homologues. However, there are a small number of genes known as “imprinted genes” that only express a single allele from one parent, which is repressed on the gene from the other parent. Imprinted genes are dependent on epigenetic mechanisms such as DNA methylation and post-translational modifications of the DNA-associated histone proteins to establish and maintain their parental identity. In the brain, multiple transcripts have been identified which show parental origin-specific expression biases. However, the mechanistic relationship with canonical imprinting is unknown. Recent studies on the postnatal neurogenic niches raise many intriguing questions concerning the role of genomic imprinting and gene dosage during postnatal neurogenesis, including how imprinted genes operate in concert with signalling cues to contribute to newborn neurons’ formation during adulthood. Here we have gathered the current knowledge on the imprinting process in the neurogenic niches. We also review the phenotypes associated with genetic mutations at particular imprinted loci in order to consider the impact of imprinted genes in the maintenance and/or differentiation of the neural stem cell pool in vivo and during brain tumour formation.
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Affiliation(s)
- Anna Lozano-Ureña
- ERI BiotecMed Departamento de Biología Celular, Universidad de Valencia, Spain
| | | | | | - Sacri R Ferrón
- ERI BiotecMed Departamento de Biología Celular, Universidad de Valencia, Spain
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24
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The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A. J Neurosci 2017; 37:10516-10527. [PMID: 28951451 DOI: 10.1523/jneurosci.1151-17.2017] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 09/10/2017] [Accepted: 09/16/2017] [Indexed: 12/23/2022] Open
Abstract
Transcription factor 4 (TCF4 also known as ITF2 or E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability, and schizophrenia (SCZ). Here, we show that TCF4-dependent transcription in cortical neurons cultured from embryonic rats of both sexes is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signaling. PKA phosphorylates TCF4 directly and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons and in the developing brain in vivo We also demonstrate that Gadd45g (growth arrest and DNA damage inducible gamma) is a direct target of neuronal-activity-induced, TCF4-dependent transcriptional regulation and that TCF4 missense variations identified in SCZ patients alter the transcriptional activity of TCF4 in neurons. This study identifies a new role for TCF4 as a neuronal-activity-regulated transcription factor, offering a novel perspective on the association of TCF4 with cognitive disorders.SIGNIFICANCE STATEMENT The importance of the basic helix-loop-helix transcription factor transcription factor 4 (TCF4) in the nervous system is underlined by its association with common and rare cognitive disorders. In the current study, we show that TCF4-controlled transcription in primary cortical neurons is induced by neuronal activity and protein kinase A. Our results support the hypotheses that dysregulation of neuronal-activity-dependent signaling plays a significant part in the etiology of neuropsychiatric and neurodevelopmental disorders.
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25
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Hennig KM, Fass DM, Zhao WN, Sheridan SD, Fu T, Erdin S, Stortchevoi A, Lucente D, Cody JD, Sweetser D, Gusella JF, Talkowski ME, Haggarty SJ. WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4. MOLECULAR NEUROPSYCHIATRY 2017; 3:53-71. [PMID: 28879201 DOI: 10.1159/000475666] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/07/2017] [Indexed: 12/11/2022]
Abstract
Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.
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Affiliation(s)
- Krista M Hennig
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel M Fass
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts, USA
| | - Wen-Ning Zhao
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
| | - Steven D Sheridan
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
| | - Ting Fu
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
| | - Serkan Erdin
- Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alexei Stortchevoi
- Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Diane Lucente
- Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jannine D Cody
- Chromosome 18 Clinical Research Center, Department of Pediatrics, University of Texas Health Sciences Center, San Antonio, Texas, USA.,The Chromosome 18 Registry and Research Society, San Antonio, Texas, USA
| | - David Sweetser
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Divisions of Pediatric Hematology/Oncology and Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - James F Gusella
- Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
| | - Michael E Talkowski
- Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Stephen J Haggarty
- Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.,Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts, USA.,Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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26
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Hill MJ, Killick R, Navarrete K, Maruszak A, McLaughlin GM, Williams BP, Bray NJ. Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex. J Psychiatry Neurosci 2017; 42:181-188. [PMID: 27689884 PMCID: PMC5403663 DOI: 10.1503/jpn.160073] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS To explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. We tested for genetic association between the set of differentially expressed genes and schizophrenia using genome-wide association study data from the Psychiatric Genomics Consortium and competitive gene set analysis (MAGMA). Effects on cell proliferation were assessed using high content imaging. RESULTS Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. There was a nonsignificant trend for genetic association between the differentially expressed gene set and schizophrenia. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. LIMITATIONS A detailed mechanistic explanation of how TCF4 knockdown alters human neural progenitor cell proliferation is not provided by this study. CONCLUSION Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in individuals with Pitt-Hopkins syndrome and risk for schizophrenia.
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Affiliation(s)
| | | | | | | | | | | | - Nicholas J. Bray
- Correspondence to: N. Bray, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Cardiff, UK;
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27
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Chen T, Wu Q, Zhang Y, Lu T, Yue W, Zhang D. Tcf4 Controls Neuronal Migration of the Cerebral Cortex through Regulation of Bmp7. Front Mol Neurosci 2016; 9:94. [PMID: 27752241 PMCID: PMC5046712 DOI: 10.3389/fnmol.2016.00094] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 09/20/2016] [Indexed: 11/14/2022] Open
Abstract
Background: Transcription factor 4 (TCF4) is found to be associated with schizophrenia. TCF4 mutations also cause Pitt-Hopkins Syndrome, a neurodevelopmental disorder associated with severe mental retardation. However, the function of TCF4 during brain development remains unclear. Results: Here, we report that Tcf4 is expressed in the developing cerebral cortex. In utero suppression of Tcf4 arrested neuronal migration, leading to accumulation of ectopic neurons in the intermediate zone. Knockdown of Tcf4 impaired leading process formation. Furthermore, Bone Morphogenetic Protein 7 (Bmp7) is upregulated in Tcf4-deficient neurons. In vivo gain of function and rescue experiments demonstrated that Bmp7 is the major downstream effector of Tcf4 required for neuronal migration. Conclusion: Thus, we have uncovered a new Tcf4/Bmp7-dependent mechanism underlying neuronal migration, and provide insights into the pathogenesis of neurodevelopmental disorders.
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Affiliation(s)
- Tianda Chen
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, BeijingChina
| | - Qinwei Wu
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Academy for Advanced Interdisciplinary Studies, Peking UniversityBeijing, China; Peking-Tsinghua Center for Life Sciences, Peking UniversityBeijing, China
| | - Yang Zhang
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, BeijingChina
| | - Tianlan Lu
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, BeijingChina
| | - Weihua Yue
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, BeijingChina
| | - Dai Zhang
- Institute of Mental Health, Peking University Sixth Hospital, BeijingChina; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, BeijingChina; Peking-Tsinghua Center for Life Sciences, Peking UniversityBeijing, China; PKU-IDG/McGovern Institute for Brain Research, Peking UniversityBeijing, China
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28
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Liu X, Huang Y, Zhang Y, Li X, Liu C, Huang S, Xu D, Wu Y, Liu X. T-cell factor (TCF/LEF1) binding elements (TBEs) of FasL (Fas ligand or CD95 ligand) bind and cluster Fas (CD95) and form complexes with the TCF-4 and b-catenin transcription factors in vitro and in vivo which result in triggering cell death and/or cell activation. Cell Mol Neurobiol 2016; 36:1001-1013. [PMID: 27090258 PMCID: PMC11482455 DOI: 10.1007/s10571-015-0290-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 10/15/2015] [Indexed: 01/02/2023]
Abstract
T-cell factor 4 (TCF4) is an important transcription factor of the Wnt signaling system. β-catenin, an upstream protein of TCF4, accumulates in the cytoplasm, then translocates to the nucleus to activate the β-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional machinery and regulates target genes. Previous studies showed that TCF4 was involved in cell proliferation and apoptosis. However, its expression and function in central nervous system injury are unclear. We performed a traumatic brain injury (TBI) model in adult rats. The expression of TCF4 in the brain cortex detected by Western blot increased after TBI. Double immunofluorescence staining revealed that TCF4 was expressed by neurons and microglia. In addition, co-localization of TCF4 with active caspase-3 or proliferating cell nuclear antigen was observed in neurons and microglia, respectively, suggesting that TCF4 might participate in neuronal apoptosis and microglial proliferation after TBI. To further investigate the functions of TCF4, PC12 and HAPI cells were employed to establish a neuronal apoptosis and microglial proliferation model in vitro, respectively. Knocking down TCF4 with siRNA proved the pro-apoptotic and pro-proliferation effect of TCF4 in PC12 and HAPI cells, respectively. Taken together, TCF4 might promote neuronal apoptosis and microglial proliferation after TBI.
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Affiliation(s)
- Xia Liu
- Department of Pathophysiology, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yuwei Huang
- Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yuanyuan Zhang
- Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Xiaohong Li
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Chun Liu
- Laboratory Animal Center, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Shen Huang
- Department of Osteology, The Second Affiliated Hospital, Nantong University, Nantong, 226001, People's Republic of China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Dezhi Xu
- Department of Neurosurgery, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214002, People's Republic of China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yang Wu
- Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
| | - Xiaojuan Liu
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
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29
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Budnick I, Hamburg-Shields E, Chen D, Torre E, Jarrell A, Akhtar-Zaidi B, Cordovan O, Spitale RC, Scacheri P, Atit RP. Defining the identity of mouse embryonic dermal fibroblasts. Genesis 2016; 54:415-30. [PMID: 27265328 DOI: 10.1002/dvg.22952] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 06/01/2016] [Accepted: 06/01/2016] [Indexed: 01/14/2023]
Abstract
Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. The gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase-seq and histone modification ChiP-seq data on various cell-types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell-types. We found a subset of the signature genes whose expression is dependent on Wnt/β-catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease. genesis 54:415-430, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Isadore Budnick
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | | | - Demeng Chen
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | - Eduardo Torre
- Epithelial Biology Program, Department of Dermatology, Stanford University, California
| | - Andrew Jarrell
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | - Batool Akhtar-Zaidi
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Olivia Cordovan
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Rob C Spitale
- Epithelial Biology Program, Department of Dermatology, Stanford University, California.,Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Peter Scacheri
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Radhika P Atit
- Department of Biology, Case Western Reserve University, Cleveland, Ohio.,Department of Pharmaceutical Sciences, University of California, Irvine, California.,Department of Dermatology, Case Western Reserve University, Cleveland, Ohio
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30
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Vega-Benedetti AF, Saucedo C, Zavattari P, Vanni R, Zugaza JL, Parada LA. PLAGL1: an important player in diverse pathological processes. J Appl Genet 2016; 58:71-78. [PMID: 27311313 DOI: 10.1007/s13353-016-0355-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 05/02/2016] [Accepted: 06/02/2016] [Indexed: 12/23/2022]
Abstract
The PLAGL1 gene encodes a homonymous zinc finger protein that promotes cell cycle arrest and apoptosis through multiple pathways. The protein has been implicated in metabolic, genetic, and neoplastic illnesses, but the molecular mechanisms by which the protein PLAGL1 participates in such diverse processes remains to be elucidated. In this review, we focus mainly on the molecular biology of PLAGL1 and the relevance of its abnormalities to several pathological processes.
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Affiliation(s)
- Ana F Vega-Benedetti
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina
| | - Cinthia Saucedo
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina
| | - Patrizia Zavattari
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Km 0.700, 09042, Monserrato, Cagliari, Italy
| | - Roberta Vanni
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Km 0.700, 09042, Monserrato, Cagliari, Italy
| | - José L Zugaza
- IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.,Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio, Spain.,Department of Genetics, Physic Anthropology and Animal Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain
| | - Luis Antonio Parada
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina.
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31
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Perez JD, Rubinstein ND, Dulac C. New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci 2016; 39:347-84. [PMID: 27145912 DOI: 10.1146/annurev-neuro-061010-113708] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mammalian evolution entailed multiple innovations in gene regulation, including the emergence of genomic imprinting, an epigenetic regulation leading to the preferential expression of a gene from its maternal or paternal allele. Genomic imprinting is highly prevalent in the brain, yet, until recently, its central roles in neural processes have not been fully appreciated. Here, we provide a comprehensive survey of adult and developmental brain functions influenced by imprinted genes, from neural development and wiring to synaptic function and plasticity, energy balance, social behaviors, emotions, and cognition. We further review the widespread identification of parental biases alongside monoallelic expression in brain tissues, discuss their potential roles in dosage regulation of key neural pathways, and suggest possible mechanisms underlying the dynamic regulation of imprinting in the brain. This review should help provide a better understanding of the significance of genomic imprinting in the normal and pathological brain of mammals including humans.
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Affiliation(s)
- Julio D Perez
- Department of Molecular and Cellular Biology, Harvard University, Howard Hughes Medical Institute, Cambridge, Massachusetts 02138;
| | - Nimrod D Rubinstein
- Department of Molecular and Cellular Biology, Harvard University, Howard Hughes Medical Institute, Cambridge, Massachusetts 02138;
| | - Catherine Dulac
- Department of Molecular and Cellular Biology, Harvard University, Howard Hughes Medical Institute, Cambridge, Massachusetts 02138;
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32
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Wasson JA, Simon AK, Myrick DA, Wolf G, Driscoll S, Pfaff SL, Macfarlan TS, Katz DJ. Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally. eLife 2016; 5. [PMID: 26814574 PMCID: PMC4829428 DOI: 10.7554/elife.08848] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 01/25/2016] [Indexed: 12/17/2022] Open
Abstract
Somatic cell nuclear transfer has established that the oocyte contains maternal factors with epigenetic reprogramming capacity. Yet the identity and function of these maternal factors during the gamete to embryo transition remains poorly understood. In C. elegans, LSD1/KDM1A enables this transition by removing H3K4me2 and preventing the transgenerational inheritance of transcription patterns. Here we show that loss of maternal LSD1/KDM1A in mice results in embryonic arrest at the 1-2 cell stage, with arrested embryos failing to undergo the maternal-to-zygotic transition. This suggests that LSD1/KDM1A maternal reprogramming is conserved. Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults. These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes. These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development. DOI:http://dx.doi.org/10.7554/eLife.08848.001 During fertilization, an egg cell and a sperm cell combine to make a cell called a zygote that then divides many times to form an embryo. Many of the characteristics of the embryo are determined by the genes it inherits from its parents. However, not all of these genes should be “expressed” to produce their products all of the time. One way of controlling gene expression is to add a chemical group called a methyl tag to the DNA near the gene, or to one of the histone proteins that DNA wraps around. Soon after fertilization, a process called reprogramming occurs that begins with the removal of most of the methyl tags a zygote inherited from the egg and sperm cells. The zygote’s DNA is then newly methylated to activate a new pattern of gene expression. In mammals, some genes escape this reprogramming; these “imprinted” genes retain the methylation patterns inherited from the parents. Reprogramming is assisted by “maternal factors” that are inherited from the egg cell. Once reprogramming is completed, the maternal factors are destroyed as part of a process called the maternal-to-zygotic transition. A maternal factor called KDM1A can remove specific methyl tags from certain histone proteins, but how this affects the zygote is not well understood. Now, Wasson et al. (and independently Ancelin et al.) have investigated the role that KDM1A plays in mouse development. Wasson et al. genetically engineered mouse egg cells to contain little or no KDM1A. Zygotes created from egg cells that completely lack KDM1A die before or shortly after they have divided for the first time and fail to undergo the maternal-to-zygotic transition. Other egg cells that contain low levels of KDM1A can give rise to baby mice. However, many of these mice die soon after birth, and those that grow to adulthood behave in abnormal ways; for example, they display excessive chewing and digging. These disorders are linked to the disruption of DNA methylation at imprinted genes. The next challenge will be to further investigate the mechanisms by which defects in maternally deposited KDM1A exert their long-range effects on imprinted genes and altered behaviour. This is particularly important because of the recent discovery of three patients with birth defects that are linked to genetic variants in KDM1A. DOI:http://dx.doi.org/10.7554/eLife.08848.002
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Affiliation(s)
- Jadiel A Wasson
- Department of Cell Biology, Emory University School of Medicine, Atlanta, United States.,Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, United States
| | - Ashley K Simon
- Department of Human Genetics, Emory University School of Medicine, Atlanta, United States
| | - Dexter A Myrick
- Department of Cell Biology, Emory University School of Medicine, Atlanta, United States.,Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, United States
| | - Gernot Wolf
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Shawn Driscoll
- Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, United States.,Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
| | - Samuel L Pfaff
- Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, United States.,Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, United States
| | - Todd S Macfarlan
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - David J Katz
- Department of Cell Biology, Emory University School of Medicine, Atlanta, United States
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Abstract
Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss- and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. Significance statement: Altered expression of imprinted genes is linked to cognitive dysfunction and neuropsychological disorders, such as Angelman and Prader-Willi syndromes, and autism spectrum disorder. Mouse models have also revealed the importance of imprinting for brain development, with chimeras generated with parthenogenetic (two maternal chromosomes) or androgenetic (two paternal chromosomes) cells displaying altered brain sizes and cellular defects. Despite these striking phenotypes, only a handful of imprinted genes are known or suspected to regulate brain development (e.g., Dlk1, Peg3, Ube3a, necdin, and Grb10). Herein we show that the maternally imprinted gene Zac1 is a critical regulator of neocortical development. Our studies are relevant because loss of 6q24 maternal imprinting in humans results in elevated ZAC1 expression, which has been associated with neurocognitive defects.
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34
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Rraklli V, Södersten E, Nyman U, Hagey DW, Holmberg J. Elevated levels of ZAC1 disrupt neurogenesis and promote rapid in vivo reprogramming. Stem Cell Res 2015; 16:1-9. [PMID: 26610203 DOI: 10.1016/j.scr.2015.11.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 10/27/2015] [Accepted: 11/09/2015] [Indexed: 01/26/2023] Open
Abstract
The zinc finger transcription factor Zac1 is expressed in dividing progenitors of the nervous system with expression levels negatively controlled by genomic imprinting. To explore the consequences of elevated ZAC1 levels during neurogenesis we overexpressed it in the developing CNS. Increased levels of ZAC1 rapidly promoted upregulation of CDK inhibitors P57 and P27 followed by cell cycle exit. Surprisingly this was accompanied by stalled neuronal differentiation. Genome wide expression analysis of cortical cells overexpressing Zac1 revealed a decrease in neuronal gene expression and an increased expression of imprinted genes, factors regulating mesoderm formation as well as features of differentiated muscle. In addition, we observed a rapid induction of several genes regulating pluripotency. Taken together, our data suggests that expression levels of Zac1 need to be kept under strict control to avoid premature cell cycle exit, disrupted neurogenesis and aberrant expression of non-neuronal genes including pluripotency associated factors.
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Affiliation(s)
- Vilma Rraklli
- Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden
| | - Erik Södersten
- Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden
| | - Ulrika Nyman
- Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden
| | - Daniel W Hagey
- Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden
| | - Johan Holmberg
- Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Nobels väg 3, 171 77, Stockholm, Sweden.
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35
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Hoffmann A, Spengler D. Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism. World J Biol Chem 2015; 6:95-109. [PMID: 26322169 PMCID: PMC4549774 DOI: 10.4331/wjbc.v6.i3.95] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/19/2015] [Accepted: 07/11/2015] [Indexed: 02/05/2023] Open
Abstract
Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.
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36
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Hoffmann A, Daniel G, Schmidt-Edelkraut U, Spengler D. Roles of imprinted genes in neural stem cells. Epigenomics 2015; 6:515-32. [PMID: 25431944 DOI: 10.2217/epi.14.42] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Imprinted genes and neural stem cells (NSC) play an important role in the developing and mature brain. A central theme of imprinted gene function in NSCs is cell survival and G1 arrest to control cell division, cell-cycle exit, migration and differentiation. Moreover, genomic imprinting can be epigenetically switched off at some genes to ensure stem cell quiescence and differentiation. At the genome scale, imprinted genes are organized in dynamic networks formed by interchromosomal interactions and transcriptional coregulation of imprinted and nonimprinted genes. Such multilayered networks may synchronize NSC activity with the demand from the niche resembling their roles in adjusting fetal size.
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Affiliation(s)
- Anke Hoffmann
- Max Planck Institute of Psychiatry, Translational Research, Kraepelinstrasse 2-10, 80804 Munich, Germany
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37
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Perez JD, Rubinstein ND, Fernandez DE, Santoro SW, Needleman LA, Ho-Shing O, Choi JJ, Zirlinger M, Chen SK, Liu JS, Dulac C. Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain. eLife 2015; 4:e07860. [PMID: 26140685 PMCID: PMC4512258 DOI: 10.7554/elife.07860] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 07/02/2015] [Indexed: 12/14/2022] Open
Abstract
The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased--rather than monoallelic--expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.
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Affiliation(s)
- Julio D Perez
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
| | - Nimrod D Rubinstein
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
| | | | - Stephen W Santoro
- Neuroscience Program, Department of Zoology and Physiology, University of Wyoming, Laramie, United States
| | - Leigh A Needleman
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
| | - Olivia Ho-Shing
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
| | - John J Choi
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
| | | | | | - Jun S Liu
- Department of Statistics, Harvard University, Cambridge, United States
| | - Catherine Dulac
- Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
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38
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Daniel G, Schmidt-Edelkraut U, Spengler D, Hoffmann A. Imprinted Zac1 in neural stem cells. World J Stem Cells 2015; 7:300-314. [PMID: 25815116 PMCID: PMC4369488 DOI: 10.4252/wjsc.v7.i2.300] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/24/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.
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39
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Iglesias-Platas I, Martin-Trujillo A, Petazzi P, Guillaumet-Adkins A, Esteller M, Monk D. Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta. Hum Mol Genet 2014; 23:6275-85. [PMID: 24993786 DOI: 10.1093/hmg/ddu347] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.
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Affiliation(s)
- Isabel Iglesias-Platas
- Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain,
| | | | - Paolo Petazzi
- Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain
| | - Amy Guillaumet-Adkins
- Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain, Imprinting and Cancer Group
| | - Manel Esteller
- Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain, Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08097, Spain and Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia 08010, Spain
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