|
1
|
Gray ZH, Honer MA, Ghatalia P, Shi Y, Whetstine JR. 20 years of histone lysine demethylases: From discovery to the clinic and beyond. Cell 2025; 188:1747-1783. [PMID: 40185081 DOI: 10.1016/j.cell.2025.02.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 04/07/2025]
Abstract
Twenty years ago, histone lysine demethylases (KDMs) were discovered. Since their discovery, they have been increasingly studied and shown to be important across species, development, and diseases. Considerable advances have been made toward understanding their (1) enzymology, (2) role as critical components of biological complexes, (3) role in normal cellular processes and functions, (4) implications in pathological conditions, and (5) therapeutic potential. This Review covers these key relationships related to the KDM field with the awareness that numerous laboratories have contributed to this field. The current knowledge coupled with future insights will shape our understanding about cell function, development, and disease onset and progression, which will allow for novel biomarkers to be identified and for optimal therapeutic options to be developed for KDM-related diseases in the years ahead.
Collapse
Affiliation(s)
- Zach H Gray
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Madison A Honer
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Pooja Ghatalia
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Yang Shi
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Johnathan R Whetstine
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
| |
Collapse
|
|
2
|
Meng Y, Wang X, Liu K, Tang X, Li H, Chen J, Zhong Z. A novel KDM5C mutation associated with intellectual disability: molecular mechanisms and clinical implications. Ital J Pediatr 2025; 51:47. [PMID: 39948613 PMCID: PMC11827480 DOI: 10.1186/s13052-025-01887-y] [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: 06/09/2024] [Accepted: 01/12/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Among the disease-causing genes associated with X-linked intellectual disability (XLID), KDM5C is one of the most frequently mutated ones. KDM5C is a widely expressed gene that is most highly expressed in the brain. KDM5C modulates the transcriptional activity of genes through demethylation of H3K4, thereby regulating neural development and normal function. We identified a gene from a Chinese family and found that a nonsense mutation of KDM5C was co-segregated with the intellectual disability (ID). METHODS The candidate mutant genes of patients with ID phenotype were screened by Whole Exome Sequencing (WES), and DNA Sanger sequencing was performed for genetic analysis. Pathogenicity prediction tools were used to evaluate the pathogenicity of new mutations. The fusion plasmid was constructed and transfected into the cells, and the changes of mRNA and protein levels of the mutants were detected by semi-qRT-PCR and Western Blot, and the subcellular localization changes of mutant proteins were detected by Immunofluorescence technique. RESULT The nonsense mutation in KDM5C (c.2785 C > T, p. R929X) was identified by whole exome sequencing (WES) and confirmed by Sanger sequencing, resulting in a truncated protein. The mutation was determined by pathogenicity prediction tool able to find non-sense mediated mRNA decay (NMD). Semi-qRT-PCR and Western Blot showed that the mRNA levels of the mutant gene were down-regulated, while the protein level was up-regulated. Additionally, the subcellular localization of the mutant protein changed. CONCLUSIONS The KDM5C mutation found in our study leads to changes in protein levels through NMD and/or protein degradation, and produces residues lacking nuclear localization, thus altering the subcellular localization of the protein. These results may lead to changes in the expression of KDM5C target genes, ultimately contributing to the clinical phenotype observed in the patients.
Collapse
Affiliation(s)
- Yunlong Meng
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xinyao Wang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Kangyu Liu
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xingkun Tang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Haining Li
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jianjun Chen
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China.
- Tongji University School of Medicine, 500 Zhennan Road Putuo District, Shanghai, 200331, China.
| | - Zilin Zhong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
- Institute of Medical Genetics, Department of Child, Adolescent and Maternal Health, School of Public Health and General Medicine, School of Medicine, Tongji University, Shanghai, 200092, China.
- Tongji University School of Medicine, 500 Zhennan Road Putuo District, Shanghai, 200331, China.
| |
Collapse
|
|
3
|
Yheskel M, Castiglione MA, Kelly RD, Sidoli S, Secombe J. The histone demethylase KDM5 has insulator activity in the brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.04.626780. [PMID: 39677601 PMCID: PMC11642926 DOI: 10.1101/2024.12.04.626780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
KDM5 family proteins are best known for their demethylation of the promoter proximal chromatin mark H3K4me3. KDM5-regulated transcription is critical in the brain, with variants in the X-linked paralog KDM5C causing the intellectual disability (ID) disorder Claes-Jensen syndrome. Although the demethylase activity of KDM5C is known to be important for neuronal function, the contribution of non-enzymatic activities remain less characterized. We therefore used Drosophila to model the ID variant Kdm5 L854F , which disrupts a C5HC2 zinc finger adjacent to the enzymatic JmjC domain. Kdm5 L854F causes similar transcriptional changes in the brain to a demethylase dead strain, Kdm5 J1310C * , despite having little effect on enzymatic activity. KDM5 L854F is also distinct from KDM5 J1310C * in its reduced interactions with insulator proteins and enhancement of position effect variegation. Instead, the common transcriptional deficits likely result from both the JmjC and C5HC2 domains driving proper genomic organization through their activity in promoting proper loop architecture.
Collapse
|
|
4
|
Nagai M, Porter RS, Miyasato M, Wang A, Gavilan CM, Hughes ED, Wu MC, Saunders TL, Iwase S. Neuronal splicing of the unmethylated histone H3K4 reader, PHF21A, prevents excessive synaptogenesis. J Biol Chem 2024; 300:107881. [PMID: 39395799 PMCID: PMC11605454 DOI: 10.1016/j.jbc.2024.107881] [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: 01/17/2024] [Revised: 08/25/2024] [Accepted: 09/16/2024] [Indexed: 10/14/2024] Open
Abstract
PHF21A is a histone-binding protein that recognizes unmethylated histone H3K4, the reaction product of LSD1 histone demethylase. PHF21A and LSD1 form a complex, and both undergo neuron-specific microexon splicing. The PHF21A neuronal microexon interferes with nucleosome binding, whereas the LSD1 neuronal microexon weakens H3K4 demethylation activity and can alter the substrate specificity to H3K9 or H4K20. However, the temporal expression patterns of PHF21A and LSD1 splicing isoforms during brain development and their biological roles remain unknown. In this work, we report that neuronal PHF21A isoform expression precedes neuronal LSD1 expression during human neuron differentiation and mouse brain development. The asynchronous splicing events resulted in stepwise deactivation of the LSD1-PHF21A complex in reversing H3K4 methylation. An unbiased proteomics survey revealed that the enzymatically inactive LSD1-PHF21A complex interacts with neuron-specific binding partners, including MYT1-family transcription factors and post-transcriptional mRNA processing proteins such as VIRMA. The interaction with the neuron-specific components, however, did not require the PHF21A microexon, indicating that the neuronal proteomic milieu, rather than the microexon-encoded PHF21A segment, is responsible for neuron-specific complex formation. Finally, by using two Phf21a mutant mouse models, we found that Phf21a neuronal splicing prevents excess synapse formation that otherwise would occur when canonical PHF21A is expressed in neurons. These results suggest that the role of the PHF21A microexon is to dampen LSD1-mediated H3K4 demethylation, thereby containing aberrant synaptogenesis.
Collapse
Affiliation(s)
- Masayoshi Nagai
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Robert S Porter
- Genetics & Genomics Graduate Program, University of Michigan, Ann Arbor, Michigan, USA
| | - Maxwell Miyasato
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA
| | - Aijia Wang
- University of Michigan College of Literature, Science, and the Arts, Ann Arbor, Michigan, USA
| | - Cecilia M Gavilan
- Genetics & Genomics Graduate Program, University of Michigan, Ann Arbor, Michigan, USA
| | - Elizabeth D Hughes
- Transgenic Animal Model Core, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Thomas L Saunders
- Transgenic Animal Model Core, University of Michigan, Ann Arbor, Michigan, USA; Division of Genetic Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Shigeki Iwase
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA.
| |
Collapse
|
|
5
|
Owens MC, Yanas A, Liu KF. Sex chromosome-encoded protein homologs: current progress and open questions. Nat Struct Mol Biol 2024; 31:1156-1166. [PMID: 39123067 DOI: 10.1038/s41594-024-01362-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/28/2024] [Indexed: 08/12/2024]
Abstract
The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the 'X-Y pairs.' The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X-Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease.
Collapse
Affiliation(s)
- Michael C Owens
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA
| | - Amber Yanas
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA
| | - Kathy Fange Liu
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
- Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA.
- Penn Center for Genome Integrity, University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
|
6
|
Honer MA, Ferman BI, Gray ZH, Bondarenko EA, Whetstine JR. Epigenetic modulators provide a path to understanding disease and therapeutic opportunity. Genes Dev 2024; 38:473-503. [PMID: 38914477 PMCID: PMC11293403 DOI: 10.1101/gad.351444.123] [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] [Indexed: 06/26/2024]
Abstract
The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.
Collapse
Affiliation(s)
- Madison A Honer
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA
| | - Benjamin I Ferman
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA
| | - Zach H Gray
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Biomedical Sciences Program, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA
| | - Elena A Bondarenko
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| | - Johnathan R Whetstine
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA;
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| |
Collapse
|
|
7
|
Li CY, Wang W, Leung CH, Yang GJ, Chen J. KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Mol Cancer 2024; 23:109. [PMID: 38769556 PMCID: PMC11103982 DOI: 10.1186/s12943-024-02011-0] [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: 02/23/2024] [Accepted: 04/29/2024] [Indexed: 05/22/2024] Open
Abstract
Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.
Collapse
Affiliation(s)
- Chang-Yun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Wanhe Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau, China.
- Macao Centre for Research and Development in Chinese Medicine, University of Macau, Macau, China.
- MoE Frontiers Science Centre for Precision Oncology, University of Macau, Macau, China.
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, Zhejiang, China.
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, Zhejiang, China.
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| |
Collapse
|
|
8
|
Nagai M, Porter RS, Hughes E, Saunders TL, Iwase S. Asynchronous microexon splicing of LSD1 and PHF21A during neurodevelopment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.21.586181. [PMID: 38562691 PMCID: PMC10983945 DOI: 10.1101/2024.03.21.586181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
LSD1 histone H3K4 demethylase and its binding partner PHF21A, a reader protein for unmethylated H3K4, both undergo neuron-specific microexon splicing. The LSD1 neuronal microexon weakens H3K4 demethylation activity and can alter the substrate specificity to H3K9 or H4K20. Meanwhile, the PHF21A neuronal microexon interferes with nucleosome binding. However, the temporal expression patterns of LSD1 and PHF21A splicing isoforms during brain development remain unknown. In this work, we report that neuronal PHF21A isoform expression precedes neuronal LSD1 isoform expression during human neuron differentiation and mouse brain development. The asynchronous splicing events resulted in stepwise deactivation of the LSD1-PHF21A complex in reversing H3K4 methylation. We further show that the enzymatically inactive LSD1-PHF21A complex interacts with neuron-specific binding partners, including MYT1-family transcription factors and post-transcriptional mRNA processing proteins such as VIRMA. The interaction with the neuron-specific components, however, did not require the PHF21A microexon, indicating that the neuronal proteomic milieu, rather than the microexon-encoded PHF21A segment, is responsible for neuron-specific complex formation. These results indicate that the PHF21A microexon is dispensable for neuron-specific protein-protein interactions, yet the enzymatically inactive LSD1-PHF21A complex might have unique gene-regulatory roles in neurons.
Collapse
Affiliation(s)
- Masayoshi Nagai
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Robert S. Porter
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Elizabeth Hughes
- Transgenic Animal Model Core, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas L. Saunders
- Transgenic Animal Model Core, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shigeki Iwase
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
9
|
Li H, Jiang W, Liu S, Yang M, Chen S, Pan Y, Cui M. Connecting the mechanisms of tumor sex differences with cancer therapy. Mol Cell Biochem 2024; 479:213-231. [PMID: 37027097 DOI: 10.1007/s11010-023-04723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 03/26/2023] [Indexed: 04/08/2023]
Abstract
Sex differences in cancer incidence and survival are constant and pronounced globally, across all races and all age groups of cancer types. In 2016, after the National Institutes of Health proposed a policy of utilizing sex as a biological variable, researchers started paying more attention to the molecular mechanisms behind gender variations in cancer. Historically, most previous studies investigating sex differences have been centered on gonadal sex hormones. Nevertheless, sex differences also involve genetic and molecular pathways that run throughout the entire process of cancer cell proliferation, metastasis, and treatment response, in addition to sex hormones. In particular, there is significant gender dimorphism in the efficacy and toxicity of oncology treatments, including conventional radiotherapy and chemotherapy, as well as the emerging targeted therapies and immunotherapy. To be clear, not all mechanisms will exhibit gender bias, and not all gender bias will affect cancer risk. Our goal in this review is to discuss some of the significant sex-related changes in fundamental cancer pathways. To this purpose, we summarize the differential impact of gender on cancer development in three dimensions: sex hormones, genetics, and epigenetics, and focus on current hot subjects including tumor suppressor function, immunology, stem cell renewal, and non-coding RNAs. Clarifying the essential mechanisms of gender differences will help guide the clinical treatment of both sexes in tumor radiation and chemotherapy, medication therapy with various targets, immunotherapy, and even drug development. We anticipate that sex-differentiated research will help advance sex-based cancer personalized medicine models and encourage future basic scientific and clinical research to take sex into account.
Collapse
Affiliation(s)
- Huan Li
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Manshi Yang
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Siyuan Chen
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Yihan Pan
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China.
| |
Collapse
|
|
10
|
Rogers MF, Marshall OJ, Secombe J. KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability in Drosophila. Development 2023; 150:dev202024. [PMID: 37800333 PMCID: PMC10651110 DOI: 10.1242/dev.202024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 09/29/2023] [Indexed: 10/07/2023]
Abstract
Histone-modifying proteins play important roles in the precise regulation of the transcriptional programs that coordinate development. KDM5 family proteins interact with chromatin through demethylation of H3K4me3 as well as demethylase-independent mechanisms that remain less understood. To gain fundamental insights into the transcriptional activities of KDM5 proteins, we examined the essential roles of the single Drosophila Kdm5 ortholog during development. KDM5 performs crucial functions in the larval neuroendocrine prothoracic gland, providing a model to study its role in regulating key gene expression programs. Integrating genome binding and transcriptomic data, we identify that KDM5 regulates the expression of genes required for the function and maintenance of mitochondria, and we find that loss of KDM5 causes morphological changes to mitochondria. This is key to the developmental functions of KDM5, as expression of the mitochondrial biogenesis transcription factor Ets97D, homolog of GABPα, is able to suppress the altered mitochondrial morphology as well as the lethality of Kdm5 null animals. Together, these data establish KDM5-mediated cellular functions that are important for normal development and could contribute to KDM5-linked disorders when dysregulated.
Collapse
Affiliation(s)
- Michael F. Rogers
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Owen J. Marshall
- Menzies Institute for Medical Research, University of Tasmania, Hobart TAS 7000, Australia
| | - Julie Secombe
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| |
Collapse
|
|
11
|
Liu H, Zhai L, Liu Y, Lu D, Vander Ark A, Yang T, Krawczyk CM. The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts. SCIENCE ADVANCES 2023; 9:eadg0731. [PMID: 37018401 PMCID: PMC10075994 DOI: 10.1126/sciadv.adg0731] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/06/2023] [Indexed: 05/28/2023]
Abstract
Women experience osteoporosis at higher rates than men. Aside from hormones, the mechanisms driving sex-dependent bone mass regulation are not well understood. Here, we demonstrate that the X-linked H3K4me2/3 demethylase KDM5C regulates sex-specific bone mass. Loss of KDM5C in hematopoietic stem cells or bone marrow monocytes increases bone mass in female but not male mice. Mechanistically, loss of KDM5C impairs the bioenergetic metabolism, resulting in impaired osteoclastogenesis. Treatment with the KDM5 inhibitor reduces osteoclastogenesis and energy metabolism of both female mice and human monocytes. Our report details a sex-dependent mechanism for bone homeostasis, connecting epigenetic regulation to osteoclast metabolism and positions KDM5C as a potential target for future treatment of osteoporosis in women.
Collapse
Affiliation(s)
- Huadie Liu
- Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
| | - Lukai Zhai
- Department of Metabolism and Nutritional Programming, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Ye Liu
- Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
| | - Di Lu
- Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
| | - Alexandra Vander Ark
- Department of Metabolism and Nutritional Programming, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Tao Yang
- Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
| | - Connie M. Krawczyk
- Department of Metabolism and Nutritional Programming, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| |
Collapse
|
|
12
|
Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable. PLoS Genet 2023; 19:e1010556. [PMID: 36802379 PMCID: PMC9942974 DOI: 10.1371/journal.pgen.1010556] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 12/06/2022] [Indexed: 02/23/2023] Open
Abstract
X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.
Collapse
|
|
13
|
Yheskel M, Sidoli S, Secombe J. Proximity labeling reveals a new in vivo network of interactors for the histone demethylase KDM5. Epigenetics Chromatin 2023; 16:8. [PMID: 36803422 PMCID: PMC9938590 DOI: 10.1186/s13072-023-00481-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND KDM5 family proteins are multi-domain regulators of transcription that when dysregulated contribute to cancer and intellectual disability. KDM5 proteins can regulate transcription through their histone demethylase activity in addition to demethylase-independent gene regulatory functions that remain less characterized. To expand our understanding of the mechanisms that contribute to KDM5-mediated transcription regulation, we used TurboID proximity labeling to identify KDM5-interacting proteins. RESULTS Using Drosophila melanogaster, we enriched for biotinylated proteins from KDM5-TurboID-expressing adult heads using a newly generated control for DNA-adjacent background in the form of dCas9:TurboID. Mass spectrometry analyses of biotinylated proteins identified both known and novel candidate KDM5 interactors, including members of the SWI/SNF and NURF chromatin remodeling complexes, the NSL complex, Mediator, and several insulator proteins. CONCLUSIONS Combined, our data shed new light on potential demethylase-independent activities of KDM5. In the context of KDM5 dysregulation, these interactions may play key roles in the alteration of evolutionarily conserved transcriptional programs implicated in human disorders.
Collapse
Affiliation(s)
- Matanel Yheskel
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Simone Sidoli
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Julie Secombe
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
| |
Collapse
|
|
14
|
Leonardi E, Aspromonte MC, Drongitis D, Bettella E, Verrillo L, Polli R, McEntagart M, Licchetta L, Dilena R, D'Arrigo S, Ciaccio C, Esposito S, Leuzzi V, Torella A, Baldo D, Lonardo F, Bonato G, Pellegrin S, Stanzial F, Posmyk R, Kaczorowska E, Carecchio M, Gos M, Rzońca-Niewczas S, Miano MG, Murgia A. Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants. Eur J Hum Genet 2023; 31:202-215. [PMID: 36434256 PMCID: PMC9905063 DOI: 10.1038/s41431-022-01233-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 10/14/2022] [Accepted: 10/31/2022] [Indexed: 11/27/2022] Open
Abstract
Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.
Collapse
Affiliation(s)
- Emanuela Leonardi
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Maria Cristina Aspromonte
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Denise Drongitis
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, Italy
| | - Elisa Bettella
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
| | - Lucia Verrillo
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, Italy
| | - Roberta Polli
- Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute, Città della Speranza, Padova, Italy
| | - Meriel McEntagart
- Medical Genetics Unit, St. George's University Hospitals, London, UK
| | - Laura Licchetta
- IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Robertino Dilena
- Neurophysiopathology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano D'Arrigo
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Claudia Ciaccio
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Silvia Esposito
- Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Vincenzo Leuzzi
- Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Annalaura Torella
- University of Campania "Luigi Vanvitelli", Caserta, Italy
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Demetrio Baldo
- Unit of medical genetics, ULSS 2 Treviso Hospital, Treviso, Italy
| | | | - Giulia Bonato
- Movement Disorders Unit, Department of Neuroscience, University of Padova, Padova, Italy
| | - Serena Pellegrin
- Child Neurology and Neurorehabilitation Unit, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - Franco Stanzial
- Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - Renata Posmyk
- Department of Clinical Genetics, Medical University in Bialystok, Bialystok, Poland
| | - Ewa Kaczorowska
- Department of Biology and Medical Genetics, Medical University of Gdansk, Gdansk, Poland
| | - Miryam Carecchio
- Movement Disorders Unit, Department of Neuroscience, University of Padova, Padova, Italy
| | - Monika Gos
- Development Genetics Laboratory, Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
| | - Sylwia Rzońca-Niewczas
- Development Genetics Laboratory, Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
| | | | - Alessandra Murgia
- Department of Women's and Children's Health, University of Padova, Padova, Italy.
- Pediatric Research Institute, Città della Speranza, Padova, Italy.
| |
Collapse
|
|
15
|
Gallardo VJ, Vila-Pueyo M, Pozo-Rosich P. The impact of epigenetic mechanisms in migraine: Current knowledge and future directions. Cephalalgia 2023; 43:3331024221145916. [PMID: 36759209 DOI: 10.1177/03331024221145916] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
BACKGROUND Epigenetic mechanisms, including DNA methylation, microRNAs and histone modifications, may modulate the genetic expression in migraine and its interaction with internal and external factors, such as lifestyle and environmental changes. OBJECTIVE To summarize, contextualize and critically analyze the published literature on the current state of epigenetic mechanisms in migraine in a narrative review. FINDINGS The studies published to date have used different approaches and methodologies to determine the role of epigenetic mechanisms in migraine. Epigenetic changes seem to be involved in migraine and are increasing our knowledge of the disease. CONCLUSIONS Changes in DNA methylation, microRNA expression and histone modifications could be utilized as biomarkers that would be highly valuable for patient stratification, molecular diagnosis, and precision medicine in migraine.
Collapse
Affiliation(s)
- Víctor José Gallardo
- Headache and Neurological Pain Research Group, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain
| | - Marta Vila-Pueyo
- Headache and Neurological Pain Research Group, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain
| | - Patricia Pozo-Rosich
- Headache and Neurological Pain Research Group, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain.,Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| |
Collapse
|
|
16
|
Ugur FS, Kelly MJS, Fujimori DG. Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability Mutations. J Mol Biol 2023; 435:167913. [PMID: 36495919 PMCID: PMC10247153 DOI: 10.1016/j.jmb.2022.167913] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/10/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
The H3K4me3 chromatin modification, a hallmark of promoters of actively transcribed genes, is dynamically removed by the KDM5 family of histone demethylases. The KDM5 demethylases have a number of accessory domains, two of which, ARID and PHD1, lie between the segments of the catalytic domain. KDM5C, which has a unique role in neural development, harbors a number of mutations adjacent to its accessory domains that cause X-linked intellectual disability (XLID). The roles of these accessory domains remain unknown, limiting an understanding of how XLID mutations affect KDM5C activity. Through in vitro binding and kinetic studies using nucleosomes, we find that while the ARID domain is required for efficient nucleosome demethylation, the PHD1 domain alone has an inhibitory role in KDM5C catalysis. In addition, the unstructured linker region between the ARID and PHD1 domains interacts with PHD1 and is necessary for nucleosome binding. Our data suggests a model in which the PHD1 domain inhibits DNA recognition by KDM5C. This inhibitory effect is relieved by the H3 tail, enabling recognition of flanking DNA on the nucleosome. Importantly, we find that XLID mutations adjacent to the ARID and PHD1 domains break this regulation by enhancing DNA binding, resulting in the loss of specificity of substrate chromatin recognition and rendering demethylase activity lower in the presence of flanking DNA. Our findings suggest a model by which specific XLID mutations could alter chromatin recognition and enable euchromatin-specific dysregulation of demethylation by KDM5C.
Collapse
Affiliation(s)
- Fatima S Ugur
- Chemistry and Chemical Biology Graduate Program, 600 16th St., San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, 600 16th St., San Francisco, CA 94158, USA
| | - Mark J S Kelly
- Department of Pharmaceutical Chemistry, 600 16th St., San Francisco, CA 94158, USA
| | - Danica Galonić Fujimori
- Department of Pharmaceutical Chemistry, 600 16th St., San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, 600 16th St., San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, 600 16th St., San Francisco, CA 94158, USA.
| |
Collapse
|
|
17
|
Shen R, Li Y, Liang A, Li S, Yang C, Huang H. A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype. BMC Neurol 2022; 22:491. [PMID: 36536324 PMCID: PMC9762001 DOI: 10.1186/s12883-022-03023-3] [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: 05/22/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Lysine(K)-specific demethylase 5C (KDM5C) dysfunction causes X-linked syndromic intellectual developmental disorder Claes-Jensen type in male patients. The clinical presentations of female individuals with heterozygous KDM5C variations vary widely and are only now beginning to be characterized in detail. CASE PRESENTATION Herein, we identified a novel de novo heterozygous nonsense variation of KDM5C (c.3533C > A, p.S1178X) in a sporadic 4-year-old Chinese girl, who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities. Moreover, X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation. CONCLUSION The report expands the genotype of KDM5C variation in female patients, delineates the phenotype of affected females in this well-known X-linked disorder, and also reinforces the necessity to consider this X-linked gene, KDM5C, in sporadic female patients.
Collapse
Affiliation(s)
- Ruiyun Shen
- grid.411609.b0000 0004 1758 4735Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Yanyang Li
- grid.256922.80000 0000 9139 560XPediatric Department, Huaihe Hospital of Henan University, Kaifeng, 475000 China
| | - Aiming Liang
- grid.411609.b0000 0004 1758 4735Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Shijie Li
- grid.411609.b0000 0004 1758 4735Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Chenlu Yang
- grid.411609.b0000 0004 1758 4735Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Hongmei Huang
- grid.411609.b0000 0004 1758 4735Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| |
Collapse
|
|
18
|
Hatch HAM, Secombe J. Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome. FEBS J 2022; 289:7776-7787. [PMID: 34536985 PMCID: PMC8930784 DOI: 10.1111/febs.16204] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/02/2021] [Accepted: 09/16/2021] [Indexed: 01/14/2023]
Abstract
The widespread availability of genetic testing for those with neurodevelopmental disorders has highlighted the importance of many genes necessary for the proper development and function of the nervous system. One gene found to be genetically altered in the X-linked intellectual disability disorder Claes-Jensen syndrome is KDM5C, which encodes a histone demethylase that regulates transcription by altering chromatin. While the genetic link between KDM5C and cognitive (dys)function is clear, how KDM5C functions to control transcriptional programs within neurons to impact their growth and activity remains the subject of ongoing research. Here, we review our current knowledge of Claes-Jensen syndrome and discuss important new data using model organisms that have revealed the importance of KDM5C in regulating aspects of neuronal development and function. Continued research into the molecular and cellular activities regulated by KDM5C is expected to provide critical etiological insights into Claes-Jensen syndrome and highlight potential targets for developing therapies to improve the quality of life of those affected.
Collapse
Affiliation(s)
- Hayden A M Hatch
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Julie Secombe
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| |
Collapse
|
|
19
|
Sawyer RP, Stone HK, Salim H, Lu X, Weirauch MT, Kottyan L. Frontotemporal degeneration genetic risk loci and transcription regulation as a possible mechanistic link to disease risk. Medicine (Baltimore) 2022; 101:e31078. [PMID: 36253972 PMCID: PMC9575772 DOI: 10.1097/md.0000000000031078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 09/12/2022] [Indexed: 11/26/2022] Open
Abstract
The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and nominate specific transcriptional regulators as potential key players in the etiology of this disease. A list of GVs associated with FTD was compiled from published GWAS. The regulatory element locus intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk GVs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation (ChIP-seq) experiments. After linkage disequilibrium expansion of the previously reported tag associated GVs, we identified 914 GV at 47 independent risk loci. Using the RELI algorithm, we identified several transcriptional regulators with enriched binding at FTD risk loci (0.05 < corrected P value <1.18 × 10-27), including Tripartite motif-containing 28 (TRIM28) and Chromodomain-Helicase DNA-binding 1 (CHD1) which have previously observed roles in FTD. FTD is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established FTD risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response as important in the genetic etiology of FTD.
Collapse
Affiliation(s)
- Russell P. Sawyer
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Hillarey K. Stone
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Hanan Salim
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Xiaoming Lu
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Matthew T. Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Leah Kottyan
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| |
Collapse
|
|
20
|
Drongitis D, Verrillo L, De Marinis P, Orabona P, Caiola A, Turitto G, Alfieri A, Bruscella S, Gentile M, Moriello V, Sannino E, Di Muccio I, Costa V, Miano MG, de Bellis A. The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme. Int J Mol Sci 2022; 23:ijms231810250. [PMID: 36142158 PMCID: PMC9498997 DOI: 10.3390/ijms231810250] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/26/2022] [Accepted: 08/31/2022] [Indexed: 11/22/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)—a negative KDM5C target—and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.
Collapse
Affiliation(s)
- Denise Drongitis
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy
- Maria Rosaria Maglione Foundation Onlus, 80122 Naples, Italy
| | - Lucia Verrillo
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy
| | - Pasqualino De Marinis
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Pasquale Orabona
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Pathology, 81100 Caserta, Italy
| | - Agnese Caiola
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Pathology, 81100 Caserta, Italy
| | - Giacinto Turitto
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Oncology, 81100 Caserta, Italy
| | - Alessandra Alfieri
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Sara Bruscella
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Marisa Gentile
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Vania Moriello
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Ettore Sannino
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Ines Di Muccio
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy
| | - Maria Giuseppina Miano
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy
- Correspondence: (M.G.M.); (A.d.B.)
| | - Alberto de Bellis
- Maria Rosaria Maglione Foundation Onlus, 80122 Naples, Italy
- A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy
- Correspondence: (M.G.M.); (A.d.B.)
| |
Collapse
|
|
21
|
Jiang CC, Lin LS, Long S, Ke XY, Fukunaga K, Lu YM, Han F. Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications. Signal Transduct Target Ther 2022; 7:229. [PMID: 35817793 PMCID: PMC9273593 DOI: 10.1038/s41392-022-01081-0] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder which has strong genetic basis. Despite the rapidly rising incidence of autism, little is known about its aetiology, risk factors, and disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism. Over the last two decades, there have been remarkable advances in genetics, with hundreds of genes identified and validated as being associated with a high risk for autism. The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism. Efforts have been devoted to exploring the behavioural functions, key pathological mechanisms and potential treatments of autism. Here, as we highlight in this review, emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription, translation, synaptic transmission, epigenetics and immunoinflammatory responses. This involvement has important implications for the discovery of precise molecular targets for autism. Moreover, we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular, cellular, neural circuit, and neurobehavioural aspects. Finally, the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.
Collapse
Affiliation(s)
- Chen-Chen Jiang
- International Joint Laboratory for Drug Target of Critical Illnesses; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Li-Shan Lin
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China
| | - Sen Long
- Department of Pharmacy, Hangzhou Seventh People's Hospital, Mental Health Center Zhejiang University School of Medicine, Hangzhou, 310013, China
| | - Xiao-Yan Ke
- Child Mental Health Research Center, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Kohji Fukunaga
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Ying-Mei Lu
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
| | - Feng Han
- International Joint Laboratory for Drug Target of Critical Illnesses; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
- Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, China.
| |
Collapse
|
|
22
|
Wang Y, Fu Y, Luo X. Identification of Pathogenetic Brain Regions via Neuroimaging Data for Diagnosis of Autism Spectrum Disorders. Front Neurosci 2022; 16:900330. [PMID: 35655751 PMCID: PMC9152096 DOI: 10.3389/fnins.2022.900330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is a kind of neurodevelopmental disorder that often occurs in children and has a hidden onset. Patients usually have lagged development of communication ability and social behavior and thus suffer an unhealthy physical and mental state. Evidence has indicated that diseases related to ASD have commonalities in brain imaging characteristics. This study aims to study the pathogenesis of ASD based on brain imaging data to locate the ASD-related brain regions. Specifically, we collected the functional magnetic resonance image data of 479 patients with ASD and 478 normal subjects matched in age and gender and used a machine-learning framework named random support vector machine cluster to extract distinctive brain regions from the preprocessed data. According to the experimental results, compared with other existing approaches, the method used in this study can more accurately distinguish patients from normal individuals based on brain imaging data. At the same time, this study found that the development of ASD was highly correlated with certain brain regions, e.g., lingual gyrus, superior frontal gyrus, medial gyrus, insular lobe, and olfactory cortex. This study explores the effectiveness of a novel machine-learning approach in the study of ASD brain imaging and provides a reference brain area for the medical research and clinical treatment of ASD.
Collapse
Affiliation(s)
- Yu Wang
- Hunan Provincial Key Laboratory of Intelligent Computing and Language Information Processing, Hunan Normal University, Changsha, China
- College of Information Science and Engineering, Hunan Normal University, Changsha, China
- Hunan Xiangjiang Artificial Intelligence Academy, Changsha, China
| | - Yu Fu
- Hunan Provincial Key Laboratory of Intelligent Computing and Language Information Processing, Hunan Normal University, Changsha, China
- College of Information Science and Engineering, Hunan Normal University, Changsha, China
- Hunan Xiangjiang Artificial Intelligence Academy, Changsha, China
- *Correspondence: Yu Fu
| | - Xun Luo
- Hunan Provincial Key Laboratory of Intelligent Computing and Language Information Processing, Hunan Normal University, Changsha, China
- College of Information Science and Engineering, Hunan Normal University, Changsha, China
- Hunan Xiangjiang Artificial Intelligence Academy, Changsha, China
| |
Collapse
|
|
23
|
Wu PM, Yu WH, Chiang CW, Wu CY, Chen JS, Tu YF. Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability. Neurol Genet 2021; 8:e646. [PMID: 34877407 PMCID: PMC8641966 DOI: 10.1212/nxg.0000000000000646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/13/2021] [Indexed: 11/15/2022]
Abstract
Background and Objectives To investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature. Methods Physical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells. Results We identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C. Discussion We report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.
Collapse
Affiliation(s)
- Po-Ming Wu
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Hao Yu
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Wu Chiang
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Yu Wu
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jia-Shing Chen
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Fang Tu
- Department of Pediatrics (P.-M.W., W.-H.Y., C.-Y.W., Y.-F.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan; School of Medicine for International Students (J.-S.C.), I-Shou University, Kaohsiung; Institute of Clinical Medicine (W.-H.Y., Y.-F.T.), College of Medicine, National Cheng Kung University, Tainan; Institute of Molecular Medicine (C.-W.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan
| |
Collapse
|
|
24
|
Hime GR, Stonehouse SLA, Pang TY. Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man. World J Psychiatry 2021; 11:711-735. [PMID: 34733638 PMCID: PMC8546770 DOI: 10.5498/wjp.v11.i10.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms-Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.
Collapse
Affiliation(s)
- Gary R Hime
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
| | - Sophie LA Stonehouse
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| | - Terence Y Pang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, VIC, Australia
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville 3052, VIC, Australia
| |
Collapse
|
|
25
|
Poeta L, Padula A, Lioi MB, van Bokhoven H, Miano MG. Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures. Genes (Basel) 2021; 12:genes12071088. [PMID: 34356104 PMCID: PMC8305412 DOI: 10.3390/genes12071088] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/22/2022] Open
Abstract
Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (KDM5C) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (ZNF711) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of ARX, KDM5C, PHF8 and ZNF711 was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments.
Collapse
Affiliation(s)
- Loredana Poeta
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy;
- Department of Science, University of Basilicata, 85100 Potenza, Italy;
- Correspondence: (L.P.); (M.G.M.); Tel.: +39-(0)-816132261/445 (M.G.M.)
| | - Agnese Padula
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy;
| | | | - Hans van Bokhoven
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, 6525 GA Nijmegen, The Netherlands;
| | - Maria Giuseppina Miano
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy;
- Correspondence: (L.P.); (M.G.M.); Tel.: +39-(0)-816132261/445 (M.G.M.)
| |
Collapse
|
|
26
|
Hatch HAM, O'Neil MH, Marion RW, Secombe J, Shulman LH. Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C. Am J Med Genet A 2021; 185:2951-2958. [PMID: 34089235 DOI: 10.1002/ajmg.a.62381] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/08/2021] [Accepted: 05/22/2021] [Indexed: 11/09/2022]
Abstract
Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7-2.8% of X-linked intellectual disability (ID) cases and pose significant burdens for patients and their caregivers. To date, 45 unique variants in KDM5C have been reported in individuals with ID. As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management. Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities. Although not as well characterized, females have been reported to predominantly display mild to moderate ID with approximately half being asymptomatic. Here, we present caregiver-reported data for 37 unrelated individuals with pathogenic variants in KDM5C; the largest cohort reported to-date. We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment. Additionally, more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum. Our data thus provide further evidence of sexually dimorphic heterogeneity in disease presentation and suggest that pathogenic variants in KDM5C may be more common than previously assumed.
Collapse
Affiliation(s)
- Hayden A M Hatch
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Molly H O'Neil
- Rose F. Kennedy Children's Evaluation and Rehabilitation Center, The Children's Hospital at Montefiore, Bronx, New York, USA
| | - Robert W Marion
- Division of Genetic Medicine, The Children's Hospital at Montefiore, Bronx, New York, USA
| | - Julie Secombe
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.,Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Lisa H Shulman
- Rose F. Kennedy Children's Evaluation and Rehabilitation Center, The Children's Hospital at Montefiore, Bronx, New York, USA
| |
Collapse
|
|
27
|
Garay PM, Chen A, Tsukahara T, Rodríguez Díaz JC, Kohen R, Althaus JC, Wallner MA, Giger RJ, Jones KS, Sutton MA, Iwase S. RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling. Cell Rep 2021; 32:108002. [PMID: 32783930 PMCID: PMC7418709 DOI: 10.1016/j.celrep.2020.108002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 06/17/2020] [Accepted: 07/15/2020] [Indexed: 12/15/2022] Open
Abstract
Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, remain incompletely characterized because most previous efforts relied on measurement of steady-state mRNAs. Here, we use nascent RNA sequencing to profile transcriptional dynamics of primary neuron cultures undergoing network activity shifts. We find pervasive transcriptional changes, in which ∼45% of expressed genes respond to network activity shifts. We further link retinoic acid-induced 1 (RAI1), the Smith-Magenis syndrome gene, to the transcriptional program driven by reduced network activity. Remarkable agreement among nascent transcriptomes, dynamic chromatin occupancy of RAI1, and electrophysiological properties of Rai1-deficient neurons demonstrates the essential roles of RAI1 in suppressing synaptic upscaling in the naive network, while promoting upscaling triggered by activity silencing. These results highlight the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.
BrU-seq reveals nascent transcription during synaptic up- or downscaling Smith-Magenis syndrome protein RAI1 regulates upscaling-associated transcription RAI1 departs chromatin in response to network activity shifts RAI1 blocks upscaling in naive networks and promotes inactivity-induced upscaling
Collapse
Affiliation(s)
- Patricia M Garay
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Alex Chen
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Takao Tsukahara
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Rafi Kohen
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - J Christian Althaus
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Margarete A Wallner
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Roman J Giger
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Kevin S Jones
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Michael A Sutton
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Shigeki Iwase
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
| |
Collapse
|
|
28
|
Shen H, Zhang W, Huang Y, He Y, Hu G, Wang L, Peng B, Yi J, Li T, Rong R, Chen X, Liu J, Li W, Ohgi K, Li S, Rosenfeld MG, Liu W. The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004635. [PMID: 33977073 PMCID: PMC8097366 DOI: 10.1002/advs.202004635] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/25/2020] [Indexed: 06/01/2023]
Abstract
Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)-target genes, and meanwhile suppresses type I interferons (IFNs) and IFN-stimulated genes (ISGs) to promote ERα-positive breast cancer cell growth and tumorigenesis. KDM5C-interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.
Collapse
Affiliation(s)
- Hai‐feng Shen
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Wen‐juan Zhang
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Ying Huang
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Yao‐hui He
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Guo‐sheng Hu
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Lei Wang
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Bing‐ling Peng
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Jia Yi
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Ting‐ting Li
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Rui Rong
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Xiao‐yan Chen
- School of Life SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Jun‐yi Liu
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Wen‐juan Li
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Kenny Ohgi
- Howard Hughes Medical InstituteDepartment of MedicineUniversity of California9500 Gilman Drive La JollaSan DiegoCA92093USA
| | - Shao‐Wei Li
- State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsXiamen UniversityXiang'an South RoadXiamenFujian361102China
| | - Michael G. Rosenfeld
- Howard Hughes Medical InstituteDepartment of MedicineUniversity of California9500 Gilman Drive La JollaSan DiegoCA92093USA
| | - Wen Liu
- State Key Laboratory of Cellular Stress BiologyFujian Provincial Key Laboratory of Innovative Drug Target ResearchSchool of Pharmaceutical SciencesXiamen UniversityXiang'an South RoadXiamenFujian361102China
| |
Collapse
|
|
29
|
Hatch HAM, Belalcazar HM, Marshall OJ, Secombe J. A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation. eLife 2021; 10:63886. [PMID: 33729157 PMCID: PMC7997662 DOI: 10.7554/elife.63886] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/16/2021] [Indexed: 02/06/2023] Open
Abstract
Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.
Collapse
Affiliation(s)
- Hayden AM Hatch
- Dominick P. Purpura Department of Neuroscience Albert Einstein College of Medicine, Bronx, United States
| | - Helen M Belalcazar
- Department of Genetics Albert Einstein College of Medicine, Bronx, United States
| | - Owen J Marshall
- Menzies Institute for Medical Research University of Tasmania, Hobart, Australia
| | - Julie Secombe
- Dominick P. Purpura Department of Neuroscience Albert Einstein College of Medicine, Bronx, United States.,Department of Genetics Albert Einstein College of Medicine, Bronx, United States
| |
Collapse
|
|
30
|
Belalcazar HM, Hendricks EL, Zamurrad S, Liebl FLW, Secombe J. The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction. Cell Rep 2021; 34:108753. [PMID: 33596422 PMCID: PMC7945993 DOI: 10.1016/j.celrep.2021.108753] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/14/2020] [Accepted: 01/25/2021] [Indexed: 02/08/2023] Open
Abstract
Mutations in the genes encoding the lysine demethylase 5 (KDM5) family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required presynaptically for neuroanatomical development and synaptic function. The Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles, is required for appropriate synaptic morphology and neurotransmission. The activity of the C5HC2 zinc finger is also required, as an ID-associated mutation in this motif reduces NMJ bouton number, increases bouton size, and alters microtubule dynamics. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene-regulatory programs.
Collapse
Affiliation(s)
- Helen M Belalcazar
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Emily L Hendricks
- Department of Biological Sciences, Southern Illinois University Edwardsville, 44 Circle Drive, Edwardsville, IL 62026, USA
| | - Sumaira Zamurrad
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Faith L W Liebl
- Department of Biological Sciences, Southern Illinois University Edwardsville, 44 Circle Drive, Edwardsville, IL 62026, USA
| | - Julie Secombe
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
| |
Collapse
|
|
31
|
Agarwal S, Bonefas KM, Garay PM, Brookes E, Murata-Nakamura Y, Porter RS, Macfarlan TS, Ren B, Iwase S. KDM1A maintains genome-wide homeostasis of transcriptional enhancers. Genome Res 2021; 31:186-197. [PMID: 33414108 PMCID: PMC7849409 DOI: 10.1101/gr.234559.118] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 12/07/2020] [Indexed: 12/27/2022]
Abstract
Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of monomethylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature of transcriptional enhancers. Lysine (K)-specific demethylase 1A (KDM1A, also known as LSD1), an H3K4me2/me1 demethylase, inactivates stem-cell enhancers during the differentiation of mouse embryonic stem cells (mESCs). However, its role in undifferentiated mESCs remains obscure. Here, we show that KDM1A actively maintains the optimal enhancer status in both undifferentiated and lineage-committed cells. KDM1A occupies a majority of enhancers in undifferentiated mESCs. KDM1A levels at enhancers exhibit clear positive correlations with its substrate H3K4me2, H3K27ac, and transcription at enhancers. In Kdm1a-deficient mESCs, a large fraction of these enhancers gains additional H3K4 methylation, which is accompanied by increases in H3K27 acetylation and increased expression of both enhancer RNAs (eRNAs) and target genes. In postmitotic neurons, loss of KDM1A leads to premature activation of neuronal activity-dependent enhancers and genes. Taken together, these results suggest that KDM1A is a versatile regulator of enhancers and acts as a rheostat to maintain optimal enhancer activity by counterbalancing H3K4 methylation at enhancers.
Collapse
Affiliation(s)
- Saurabh Agarwal
- Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, California 92093-0653, USA
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Katherine M Bonefas
- Neuroscience Graduate Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Patricia M Garay
- Neuroscience Graduate Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Emily Brookes
- Division of Newborn Medicine, Boston Children's Hospital, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Yumie Murata-Nakamura
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Robert S Porter
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Todd S Macfarlan
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Bing Ren
- Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, California 92093-0653, USA
| | - Shigeki Iwase
- Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA
| |
Collapse
|
|
32
|
Thongkorn S, Kanlayaprasit S, Panjabud P, Saeliw T, Jantheang T, Kasitipradit K, Sarobol S, Jindatip D, Hu VW, Tencomnao T, Kikkawa T, Sato T, Osumi N, Sarachana T. Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions. Sci Rep 2021; 11:1241. [PMID: 33441873 PMCID: PMC7806752 DOI: 10.1038/s41598-020-80390-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/21/2020] [Indexed: 01/29/2023] Open
Abstract
Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.
Collapse
Affiliation(s)
- Surangrat Thongkorn
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Songphon Kanlayaprasit
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Pawinee Panjabud
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Thanit Saeliw
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Thanawin Jantheang
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Kasidit Kasitipradit
- grid.7922.e0000 0001 0244 7875The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Suthathip Sarobol
- grid.411628.80000 0000 9758 8584Specimen Center, Department of Laboratory Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Depicha Jindatip
- grid.7922.e0000 0001 0244 7875Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand ,grid.7922.e0000 0001 0244 7875SYstems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Valerie W. Hu
- grid.253615.60000 0004 1936 9510Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, The George Washington University, Washington, DC USA
| | - Tewin Tencomnao
- grid.7922.e0000 0001 0244 7875Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Takako Kikkawa
- grid.69566.3a0000 0001 2248 6943Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan
| | - Tatsuya Sato
- grid.412754.10000 0000 9956 3487Department of Healthcare Management, Faculty of Health Sciences, Tohoku Fukushi University, Sendai, Miyagi Japan
| | - Noriko Osumi
- grid.69566.3a0000 0001 2248 6943Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai, Miyagi Japan
| | - Tewarit Sarachana
- grid.7922.e0000 0001 0244 7875SYstems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand ,grid.7922.e0000 0001 0244 7875Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
33
|
El Hayek L, Tuncay IO, Nijem N, Russell J, Ludwig S, Kaur K, Li X, Anderton P, Tang M, Gerard A, Heinze A, Zacher P, Alsaif HS, Rad A, Hassanpour K, Abbaszadegan MR, Washington C, DuPont BR, Louie RJ, Couse M, Faden M, Rogers RC, Abou Jamra R, Elias ER, Maroofian R, Houlden H, Lehman A, Beutler B, Chahrour MH. KDM5A mutations identified in autism spectrum disorder using forward genetics. eLife 2020; 9:56883. [PMID: 33350388 PMCID: PMC7755391 DOI: 10.7554/elife.56883] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 12/06/2020] [Indexed: 12/29/2022] Open
Abstract
Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.
Collapse
Affiliation(s)
- Lauretta El Hayek
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
| | - Islam Oguz Tuncay
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
| | - Nadine Nijem
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
| | - Jamie Russell
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Sara Ludwig
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Kiran Kaur
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
| | - Xiaohong Li
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Priscilla Anderton
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Miao Tang
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Amanda Gerard
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.,Texas Children's Hospital, Houston, United States
| | - Anja Heinze
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Pia Zacher
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
| | - Hessa S Alsaif
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Aboulfazl Rad
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran
| | - Kazem Hassanpour
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran
| | - Mohammad Reza Abbaszadegan
- Pardis Clinical and Genetics Laboratory, Mashhad, Islamic Republic of Iran.,Division of Human Genetics, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran
| | | | | | | | -
- Department of Medical Genetics, University of British Columbia, British Columbia Children's and Women's Hospital Research Institute, Vancouver, Canada
| | - Madeline Couse
- Department of Medical Genetics, University of British Columbia, British Columbia Children's and Women's Hospital Research Institute, Vancouver, Canada
| | - Maha Faden
- Department of Genetics, King Saud Medical City, Riyadh, Saudi Arabia
| | | | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Ellen R Elias
- Department of Pediatrics and Genetics, University of Colorado School of Medicine, Aurora, United States
| | - Reza Maroofian
- Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom
| | - Henry Houlden
- Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, United Kingdom
| | - Anna Lehman
- Department of Medical Genetics, University of British Columbia, British Columbia Children's and Women's Hospital Research Institute, Vancouver, Canada
| | - Bruce Beutler
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
| | - Maria H Chahrour
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States.,Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States.,Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, United States
| |
Collapse
|
|
34
|
Zhang M, Zhao J, Lv Y, Wang W, Feng C, Zou W, Su L, Jiao J. Histone Variants and Histone Modifications in Neurogenesis. Trends Cell Biol 2020; 30:869-880. [PMID: 33011018 DOI: 10.1016/j.tcb.2020.09.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 12/20/2022]
Abstract
During embryonic brain development, neurogenesis requires the orchestration of gene expression to regulate neural stem cell (NSC) fate specification. Epigenetic regulation with specific emphasis on the modes of histone variants and histone post-translational modifications are involved in interactive gene regulation of central nervous system (CNS) development. Here, we provide a broad overview of the regulatory system of histone variants and histone modifications that have been linked to neurogenesis and diseases. We also review the crosstalk between different histone modifications and discuss how the 3D genome affects cell fate dynamics during brain development. Understanding the mechanisms of epigenetic regulation in neurogenesis has shifted the paradigm from single gene regulation to synergistic interactions to ensure healthy embryonic neurogenesis.
Collapse
Affiliation(s)
- Mengtian Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jinyue Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuqing Lv
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenwen Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Science and Technology of China, Hefei 230000, China
| | - Chao Feng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenzheng Zou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Libo Su
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianwei Jiao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| |
Collapse
|
|
35
|
Farajollahi Z, Razmara E, Heidari E, Jafarinia E, Garshasbi M. A novel variant of ST3GAL3 causes non-syndromic autosomal recessive intellectual disability in Iranian patients. J Gene Med 2020; 22:e3253. [PMID: 32666583 DOI: 10.1002/jgm.3253] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/01/2020] [Accepted: 07/09/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The number of reported genes causing non-syndromic autosomal recessive intellectual disability (NS-ARID) is increasing. For example, mutations in the ST3GAL3 gene have been reported to be associated with NS-ARID. In the present study, we aimed to determine the genetic cause of the NS-ARID in a five-generation consanguineous Iranian family. METHODS We subjected four patients with an initial diagnosis of NS-ID in an Iranian family. To identify the possible genetic cause(s), whole-exome sequencing was performed on the proband and Sanger sequencing was applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ST3Gal-III were predicted. RESULTS The common clinical features were detected in all affected members who were suffering from a severe ID. Using whole-exome sequencing, a novel variant, c.704C>T or p.(Thr235Met), in exon 9 of the ST3GAL3 gene (NM_001270461.2, OMIM# 606494) was identified and verified by Sanger sequencing. This variant is located next to the VS motif of ST3Gal-III, which is a vital part of the catalytical domains. CONCLUSIONS In the present study, we identified a novel missense variant, c.704C>T or p.(Thr235Met), in the ST3GAL3. To our knowledge, is the third variant in this gene to be associated with NS-ARID. Our findings highlight the need for further investigations into the mechanisms by which variants in ST3GAL3 contribute to neurological dysfunction.
Collapse
Affiliation(s)
- Zahra Farajollahi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Erfan Heidari
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Jafarinia
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
36
|
Tricarico R, Nicolas E, Hall MJ, Golemis EA. X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis. Clin Cancer Res 2020; 26:5567-5578. [PMID: 32732223 DOI: 10.1158/1078-0432.ccr-20-1741] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/24/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022]
Abstract
Biological sex profoundly conditions organismal development and physiology, imposing wide-ranging effects on cell signaling, metabolism, and immune response. These effects arise from sex-specified differences in hormonal exposure, and from intrinsic genetic and epigenetic differences associated with the presence of an XX versus XY chromosomal complement. In addition, biological sex is now recognized to be a determinant of the incidence, presentation, and therapeutic response of multiple forms of cancer, including cancers not specifically associated with male or female anatomy. Although multiple factors contribute to sex-based differences in cancer, a growing body of research emphasizes a role for differential activity of X- and Y-linked tumor-suppressor genes in males and females. Among these, the X-linked KDM6A/UTX and KDM5C/JARID1C/SMCX, and their Y-linked paralogs UTY/KDM6C and KDM5D/JARID1D/SMCY encode lysine demethylases. These epigenetic modulators profoundly influence gene expression, based on enzymatic activity in demethylating H3K27me3 and H3K4me3, and nonenzymatic scaffolding roles for large complexes that open and close chromatin for transcription. In a growing number of cases, mutations affecting these proteins have been recognized to strongly influence cancer risk, prognosis, and response to specific therapies. However, sex-specific patterns of mutation, expression, and activity of these genes, coupled with tissue-specific requirement for their function as tumor suppressors, together exemplify the complex relationship between sex and cancer vulnerabilities. In this review, we summarize and discuss the current state of the literature on the roles of these proteins in contributing to sex bias in cancer, and the status of clinical agents relevant to their function.
Collapse
Affiliation(s)
- Rossella Tricarico
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. .,Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Emmanuelle Nicolas
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Michael J Hall
- Cancer Prevention and Control Program, Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Erica A Golemis
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
| |
Collapse
|
|
37
|
Poeta L, Padula A, Attianese B, Valentino M, Verrillo L, Filosa S, Shoubridge C, Barra A, Schwartz CE, Christensen J, van Bokhoven H, Helin K, Lioi MB, Collombat P, Gecz J, Altucci L, Di Schiavi E, Miano MG. Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders. Hum Mol Genet 2020; 28:4089-4102. [PMID: 31691806 DOI: 10.1093/hmg/ddz254] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 12/26/2022] Open
Abstract
A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.
Collapse
Affiliation(s)
- Loredana Poeta
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Agnese Padula
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy.,University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Benedetta Attianese
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Mariaelena Valentino
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Lucia Verrillo
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy.,University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Stefania Filosa
- Institute of Biosciences and BioResources, National Research Council (CNR), Naples, Italy.,Istituto Neurologico Mediterraneo (Neuromed), Pozzilli, Isernia, Italy
| | - Cheryl Shoubridge
- Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.,Robinson Research Institute, Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia
| | - Adriano Barra
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | | | - Jesper Christensen
- University of Copenhagen, Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.,University of Copenhagen, The Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), Copenhagen, Denmark
| | - Hans van Bokhoven
- Department of Human Genetics, Donders Institute for Brain, Behaviour and Cognition, Radboudumc, Nijmegen, The Netherlands
| | - Kristian Helin
- University of Copenhagen, Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.,University of Copenhagen, The Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), Copenhagen, Denmark
| | | | | | - Jozef Gecz
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
| | - Lucia Altucci
- University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Elia Di Schiavi
- Institute of Biosciences and BioResources, National Research Council (CNR), Naples, Italy
| | - Maria Giuseppina Miano
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| |
Collapse
|
|
38
|
Arifuzzaman S, Khatun MR, Khatun R. Emerging of lysine demethylases (KDMs): From pathophysiological insights to novel therapeutic opportunities. Biomed Pharmacother 2020; 129:110392. [PMID: 32574968 DOI: 10.1016/j.biopha.2020.110392] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 06/06/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, there have been remarkable scientific advancements in the understanding of lysine demethylases (KDMs) because of their demethylation of diverse substrates, including nucleic acids and proteins. Novel structural architectures, physiological roles in the gene expression regulation, and ability to modify protein functions made KDMs the topic of interest in biomedical research. These structural diversities allow them to exert their function either alone or in complex with numerous other bio-macromolecules. Impressive number of studies have demonstrated that KDMs are localized dynamically across the cellular and tissue microenvironment. Their dysregulation is often associated with human diseases, such as cancer, immune disorders, neurological disorders, and developmental abnormalities. Advancements in the knowledge of the underlying biochemistry and disease associations have led to the development of a series of modulators and technical compounds. Given the distinct biophysical and biochemical properties of KDMs, in this review we have focused on advances related to the structure, function, disease association, and therapeutic targeting of KDMs highlighting improvements in both the specificity and efficacy of KDM modulation.
Collapse
Affiliation(s)
- Sarder Arifuzzaman
- Department of Pharmacy, Jahangirnagar University, Dhaka-1342, Bangladesh; Everest Pharmaceuticals Ltd., Dhaka-1208, Bangladesh.
| | - Mst Reshma Khatun
- Department of Pharmacy, Jahangirnagar University, Dhaka-1342, Bangladesh
| | - Rabeya Khatun
- Department of Pediatrics, TMSS Medical College and Rafatullah Community Hospital, Gokul, Bogura, 5800, Bangladesh
| |
Collapse
|
|
39
|
Vallianatos CN, Raines B, Porter RS, Bonefas KM, Wu MC, Garay PM, Collette KM, Seo YA, Dou Y, Keegan CE, Tronson NC, Iwase S. Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation. Commun Biol 2020; 3:278. [PMID: 32483278 PMCID: PMC7264178 DOI: 10.1038/s42003-020-1001-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 05/09/2020] [Indexed: 12/17/2022] Open
Abstract
Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.
Collapse
Affiliation(s)
- Christina N Vallianatos
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.,Genetics and Genomics Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Brynne Raines
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Robert S Porter
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.,Genetics and Genomics Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Katherine M Bonefas
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.,The University of Michigan Neuroscience Graduate Program, Ann Arbor, MI, USA
| | | | - Patricia M Garay
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.,The University of Michigan Neuroscience Graduate Program, Ann Arbor, MI, USA
| | - Katie M Collette
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Young Ah Seo
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yali Dou
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Catherine E Keegan
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.,Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Natalie C Tronson
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Shigeki Iwase
- Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
| |
Collapse
|
|
40
|
Carmignac V, Nambot S, Lehalle D, Callier P, Moortgat S, Benoit V, Ghoumid J, Delobel B, Smol T, Thuillier C, Zordan C, Naudion S, Bienvenu T, Touraine R, Ramond F, Zweier C, Reis A, Kraus C, Nizon M, Cogné B, Verloes A, Tran Mau‐Them F, Sorlin A, Jouan T, Duffourd Y, Tisserant E, Philippe C, Vitobello A, Thevenon J, Faivre L, Thauvin‐Robinet C. Further delineation of the female phenotype with
KDM5C
disease causing variants: 19 new individuals and review of the literature. Clin Genet 2020; 98:43-55. [DOI: 10.1111/cge.13755] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Virginie Carmignac
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Centre de Référence Maladies Génétique à Expression Cutanée Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Sophie Nambot
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Daphné Lehalle
- Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Patrick Callier
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Stephanie Moortgat
- Centre de Génétique Humaine Institut de Pathologie et de Génétique Charleroi Belgium
| | - Valérie Benoit
- Centre de Génétique Humaine Institut de Pathologie et de Génétique Charleroi Belgium
| | - Jamal Ghoumid
- CHU Lille, Clinique de Génétique – Guy Fontaine Lille France
- Université Lille EA 7364 – RADEME ‐ Maladies RAres du DEveloppement embryonnaire et du MEtabolisme Lille France
| | - Bruno Delobel
- Centre de Génétique Chromosomique GHICL, Hôpital Saint Vincent de Paul Lille France
| | - Thomas Smol
- Université Lille EA 7364 – RADEME ‐ Maladies RAres du DEveloppement embryonnaire et du MEtabolisme Lille France
- CHU Lille Institut de Génétique Médicale Lille France
| | | | - Cécile Zordan
- Service de Génétique clinique Centre Hospitalier Universitaire de Bordeaux Bordeaux France
| | - Sophie Naudion
- Service de Génétique clinique Centre Hospitalier Universitaire de Bordeaux Bordeaux France
| | - Thierry Bienvenu
- Institut de Psychiatrie et de Neurosciences de Paris Inserm U1266 Paris France
- Université de Paris Paris France
- Assistance Publique‐Hôpitaux de Paris, Groupe Universitaire Paris Centre, Site Cochin Laboratoire de Biochimie et Génétique Moléculaires Paris France
| | - Renaud Touraine
- Service de Génétique Clinique, Chromosomique et Moléculaire Centre de Référence des Anomalies du Développement, CHU de Saint‐Etienne Saint‐Priest‐en‐Jarez France
| | - Francis Ramond
- Service de Génétique Clinique, Chromosomique et Moléculaire Centre de Référence des Anomalies du Développement, CHU de Saint‐Etienne Saint‐Priest‐en‐Jarez France
| | - Christiane Zweier
- Institute of Human Genetics Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | - André Reis
- Institute of Human Genetics Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | - Cornelia Kraus
- Institute of Human Genetics Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | | | | | - Alain Verloes
- Département de Génétique Hôpital Robert Debré Paris France
| | - Frédéric Tran Mau‐Them
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Arthur Sorlin
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Thibaud Jouan
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
| | - Yannis Duffourd
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Emilie Tisserant
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Christophe Philippe
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Antonio Vitobello
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| | - Julien Thevenon
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Laurence Faivre
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Centre de Génétique et Centre de référence « Anomalies du Développement et Syndromes Malformatifs », Hôpital d'Enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
| | - Christel Thauvin‐Robinet
- INSERM UMR1231, Equipe Génétique des Anomalies du Développement Université de Bourgogne Dijon France
- Unité Fonctionnelle « Diagnostic en innovation génomique des maladies rares » Laboratoire de Génétique Chromosomique et Moléculaire, Plateau Technique de Biologie Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
- Fédération Hospitalo‐Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD) Centre Hospitalier Universitaire de Dijon et Université de Bourgogne‐Franche Comté Dijon France
- Centre de référence maladies rares « déficience intellectuelle de causes rares », Hôpital d'enfants Centre Hospitalier Universitaire Dijon Bourgogne Dijon France
| |
Collapse
|
|
41
|
Helman G, Lajoie BR, Crawford J, Takanohashi A, Walkiewicz M, Dolzhenko E, Gross AM, Gainullin VG, Bent SJ, Jenkinson EM, Ferdinandusse S, Waterham HR, Dorboz I, Bertini E, Miyake N, Wolf NI, Abbink TEM, Kirwin SM, Tan CM, Hobson GM, Guo L, Ikegawa S, Pizzino A, Schmidt JL, Bernard G, Schiffmann R, van der Knaap MS, Simons C, Taft RJ, Vanderver A. Genome sequencing in persistently unsolved white matter disorders. Ann Clin Transl Neurol 2020; 7:144-152. [PMID: 31912665 PMCID: PMC6952322 DOI: 10.1002/acn3.50957] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/05/2019] [Accepted: 11/05/2019] [Indexed: 01/01/2023] Open
Abstract
Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.
Collapse
Affiliation(s)
- Guy Helman
- Murdoch Children's Research InstituteThe Royal Children's Hospital MelbourneParkville, MelbourneAustralia
- Institute for Molecular BioscienceThe University of QueenslandBrisbaneAustralia
| | | | - Joanna Crawford
- Institute for Molecular BioscienceThe University of QueenslandBrisbaneAustralia
| | - Asako Takanohashi
- Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaPennsylvania
| | - Marzena Walkiewicz
- Murdoch Children's Research InstituteThe Royal Children's Hospital MelbourneParkville, MelbourneAustralia
| | | | | | | | - Stephen J. Bent
- Data61Commonwealth Scientific and Industrial Research OrganisationBrisbaneAustralia
| | - Emma M. Jenkinson
- Faculty of Biology, Medicine and HealthSchool of Biological SciencesDivision of Evolution and Genomic SciencesUniversity of ManchesterManchesterUnited Kingdom
| | - Sacha Ferdinandusse
- Laboratory Genetic Metabolic DiseasesDepartment of Clinical ChemistryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Hans R. Waterham
- Laboratory Genetic Metabolic DiseasesDepartment of Clinical ChemistryAmsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Imen Dorboz
- INSERM UMR 1141DHU PROTECTUniversité Paris Diderot‐ SorbonneParis CitéFrance
| | - Enrico Bertini
- Unit of Neuromuscular and Neurodegenerative DisordersLaboratory of Molecular MedicineBambino Gesu' Children's HospitalRomeItaly
- Genetics and Rare Diseases Research DivisionOspedale Pediatrico Bambino Gesù00146RomeItaly
| | - Noriko Miyake
- Department of Human GeneticsYokohama City University Graduate School of MedicineFukuura, Kanazawa‐kuYokohama236‐0004Japan
| | - Nicole I. Wolf
- Department of Child NeurologyEmma Children’s HospitalAmsterdam University Medical CentersVrije Universiteit Amsterdam and Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Truus E. M. Abbink
- Department of Child NeurologyEmma Children’s HospitalAmsterdam University Medical CentersVrije Universiteit Amsterdam and Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Susan M. Kirwin
- Molecular Diagnostics LaboratoryNemours Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonDelaware
| | - Christina M. Tan
- Molecular Diagnostics LaboratoryNemours Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonDelaware
| | - Grace M. Hobson
- Molecular Diagnostics LaboratoryNemours Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonDelaware
| | - Long Guo
- Laboratory of Bone and Joint DiseasesRIKEN Center for Integrative Medical SciencesTokyoJapan
| | - Shiro Ikegawa
- Laboratory of Bone and Joint DiseasesRIKEN Center for Integrative Medical SciencesTokyoJapan
| | - Amy Pizzino
- Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaPennsylvania
| | - Johanna L. Schmidt
- Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaPennsylvania
| | - Genevieve Bernard
- Departments of Neurology and Neurosurgery, Pediatrics, and Human GeneticsMcGill UniversityMontrealCanada
- Division of Medical GeneticsMontreal Children’s HospitalMcGill University Health CenterMontrealCanada
- Child Health and Human Development ProgramResearch Institute of the McGill University Health CenterMontrealCanada
| | - Raphael Schiffmann
- Institute of Metabolic DiseaseBaylor Scott & White Research InstituteDallasTexas
| | - Marjo S. van der Knaap
- Department of Child NeurologyEmma Children’s HospitalAmsterdam University Medical CentersVrije Universiteit Amsterdam and Amsterdam NeuroscienceAmsterdamThe Netherlands
- Department of Functional GenomicsAmsterdam NeuroscienceVU UniversityAmsterdamthe Netherlands
| | - Cas Simons
- Murdoch Children's Research InstituteThe Royal Children's Hospital MelbourneParkville, MelbourneAustralia
- Institute for Molecular BioscienceThe University of QueenslandBrisbaneAustralia
| | | | - Adeline Vanderver
- Division of NeurologyChildren’s Hospital of PhiladelphiaPhiladelphiaPennsylvania
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvania
| |
Collapse
|
|
42
|
Drelon C, Rogers MF, Belalcazar HM, Secombe J. The histone demethylase KDM5 controls developmental timing in Drosophila by promoting prothoracic gland endocycles. Development 2019; 146:dev.182568. [PMID: 31862793 PMCID: PMC6955219 DOI: 10.1242/dev.182568] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022]
Abstract
In Drosophila, the larval prothoracic gland integrates nutritional status with developmental signals to regulate growth and maturation through the secretion of the steroid hormone ecdysone. While the nutritional signals and cellular pathways that regulate prothoracic gland function are relatively well studied, the transcriptional regulators that orchestrate the activity of this tissue remain less characterized. Here, we show that lysine demethylase 5 (KDM5) is essential for prothoracic gland function. Indeed, restoring kdm5 expression only in the prothoracic gland in an otherwise kdm5 null mutant animal is sufficient to rescue both the larval developmental delay and the pupal lethality caused by loss of KDM5. Our studies show that KDM5 functions by promoting the endoreplication of prothoracic gland cells, a process that increases ploidy and is rate limiting for the expression of ecdysone biosynthetic genes. Molecularly, we show that KDM5 activates the expression of the receptor tyrosine kinase torso, which then promotes polyploidization and growth through activation of the MAPK signaling pathway. Taken together, our studies provide key insights into the biological processes regulated by KDM5 and expand our understanding of the transcriptional regulators that coordinate animal development. Summary: Identification of KDM5 as a new transcriptional regulator of the MAPK signaling cascade provides insights into the molecular mechanisms governing the regulation of ecdysone production and developmental growth control.
Collapse
Affiliation(s)
- Coralie Drelon
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Michael F Rogers
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Helen M Belalcazar
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Julie Secombe
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA .,Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA
| |
Collapse
|
|
43
|
The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med 2019; 51:1-17. [PMID: 31221981 PMCID: PMC6586683 DOI: 10.1038/s12276-019-0230-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/12/2018] [Indexed: 12/16/2022] Open
Abstract
Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type. Genes involved in the removal of methyl groups from histones associated with DNA can promote or suppress tumor growth depending on the metabolic status of the cancer cell. Hyunsung Park and colleagues at the University of Seoul, South Korea, review current knowledge of two genes encoding histone demethylases which have been identified by The Cancer Genome Atlas (TCGA) project as cancer driver genes. Because these demethylase enzymes rely on cellular metabolites to function, their effect is influenced by metabolic conditions in the tumor microenvironment such as low oxygen. The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown. Further understanding of how cancer metabolism affects the modification of histones will help guide the development of more effective cancer treatments.
Collapse
|
|
44
|
Bludau A, Royer M, Meister G, Neumann ID, Menon R. Epigenetic Regulation of the Social Brain. Trends Neurosci 2019; 42:471-484. [PMID: 31103351 DOI: 10.1016/j.tins.2019.04.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/10/2019] [Accepted: 04/12/2019] [Indexed: 12/17/2022]
Abstract
Social behavior, a highly adaptive and crucial component of mammalian life, is regulated by particularly sensitive regulatory brain mechanisms. Substantial evidence implicates classical epigenetic mechanisms including histone modifications, DNA methylation, and nucleosome remodeling as well as nonclassical mechanisms mediated by noncoding RNA in the regulation of social behavior. These mechanisms collectively form the 'epigenetic network' that orchestrates genomic integration of salient and transient social experiences. Consequently, its dysregulation has been linked to behavioral deficits and psychopathologies. This review focuses on the role of the epigenetic network in regulating the enduring effects of social experiences during early-life, adolescence, and adulthood. We discuss research in animal models, primarily rodents, and associations between dysregulation of epigenetic mechanisms and human psychopathologies, specifically autism spectrum disorder (ASD) and schizophrenia.
Collapse
Affiliation(s)
- Anna Bludau
- Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany
| | - Melanie Royer
- Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany; Biochemistry Center Regensburg (BZR), Laboratory of RNA Biology, University of Regensburg, Regensburg, Germany
| | - Gunter Meister
- Biochemistry Center Regensburg (BZR), Laboratory of RNA Biology, University of Regensburg, Regensburg, Germany
| | - Inga D Neumann
- Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany
| | - Rohit Menon
- Department of Behavioral and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
| |
Collapse
|
|
45
|
Swahari V, West AE. Histone demethylases in neuronal differentiation, plasticity, and disease. Curr Opin Neurobiol 2019; 59:9-15. [PMID: 30878844 DOI: 10.1016/j.conb.2019.02.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 02/14/2019] [Indexed: 12/29/2022]
Abstract
For more than 40 years after its discovery, histone methylation was thought to be largely irreversible. However, the first histone demethylase (HDM) was identified in 2004, challenging this notion. Since that time, more than 20 HDMs have been identified and characterized, and many have been shown to have critical roles in organismal development, cell fate, and disease. Here, we highlight some of the recent advances in our understanding of the function of HDMs in the context of neuronal development, plasticity, and disease. We focus, in particular, on molecular genetic studies of LSD1, Kdm6b, and Kdm5c that have elucidated both enzymatic and non-enzymatic gene regulatory functions of these HDMs in neurons.
Collapse
Affiliation(s)
- Vijay Swahari
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Anne E West
- Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
| |
Collapse
|
|
46
|
Alagoz M, Kherad N, Gavaz M, Yuksel A. New Genetic Approaches for Early Diagnosis and Treatment of Autism Spectrum Disorders. REVIEW JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS 2019. [DOI: 10.1007/s40489-019-00167-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
|
|
47
|
Gong J, Yan S, Yu H, Zhang W, Zhang D. Increased Expression of Lysine-Specific Demethylase 5B (KDM5B) Promotes Tumor Cell Growth in Hep3B Cells and is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma. Med Sci Monit 2018; 24:7586-7594. [PMID: 30353907 PMCID: PMC6210936 DOI: 10.12659/msm.910844] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 05/08/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Lysine-specific demethylase 5B (KDM5B) is overexpressed in several types of cancer. However, the clinical significance of KDM5B expression in hepatocellular carcinoma (HCC) remains unclear. The aims of the present study were to examine the functional effects of KDM5B in the Hep3B cell line, the expression levels of KDM5B in human HCC tissues, and the association between KDM5B expression and clinical outcome in patients with HCC. MATERIAL AND METHODS Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression levels of KDM5B in HCC tissues and adjacent normal liver tissues. In the HCC cell line, Hep3B, the effects of KDM5B on cell proliferation and migration, and KDM5B small interfering RNA (siRNA) were used to study KDM5B knockdown. Univariate and multivariate analysis assessed the prognostic role of KDM5B in HCC patients. Kaplan-Meier analysis and the log-rank test evaluated clinical outcomes. RESULTS In the HCC cell line, Hep3B, KDM5B expression promoted promote tumor cell proliferation and colony formation. Increased expression of KDM5B in HCC tissues, compared with adjacent normal liver tissues, and was associated with larger tumor size, advanced TNM stage, and reduced overall survival in patients with HCC. Multivariate analysis identified KDM5B expression as an independent prognostic factor. CONCLUSIONS Increased expression of KDM5B was significantly correlated with poorer prognosis in patients with patients with HCC, indicating the possible potential of KDM5B as a novel clinical biomarker and therapeutic target.
Collapse
Affiliation(s)
- Jian Gong
- Department of Infectious Disease, The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Shuyuan Yan
- Child Health Care Center, Changsha Hospital for Maternal and Child Health Care, Changsha, Hunan, P.R. China
| | - Hui Yu
- Child Health Care Center, Changsha Hospital for Maternal and Child Health Care, Changsha, Hunan, P.R. China
| | - Wenhua Zhang
- Department of Ophthalmology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | - Di Zhang
- Department of Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| |
Collapse
|
|
48
|
The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila. Genetics 2018; 209:773-787. [PMID: 29764901 PMCID: PMC6028249 DOI: 10.1534/genetics.118.301004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 05/11/2018] [Indexed: 02/07/2023] Open
Abstract
Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and -independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for viability. Animals lacking KDM5 show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in wing imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our analyses reveal KDM5 as a key regulator of larval growth and offer an invaluable tool for defining the biological activities of KDM5 family proteins.
Collapse
|