Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders
Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their eti...
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MDPI AG
2020-11-01
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| author | Swati Maitra Nitin Khandelwal Scherazad Kootar Pooja Sant Salil S. Pathak Sujatha Reddy Annapoorna P. K. Upadhyayula Suryanarayana Murty Sumana Chakravarty Arvind Kumar |
| author_facet | Swati Maitra Nitin Khandelwal Scherazad Kootar Pooja Sant Salil S. Pathak Sujatha Reddy Annapoorna P. K. Upadhyayula Suryanarayana Murty Sumana Chakravarty Arvind Kumar |
| author_sort | Swati Maitra |
| collection | DOAJ |
| description | Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and <i>ex vivo</i> DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of <i>Id2</i> (inhibitor of differentiation 2) and <i>Sox2</i> (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure. |
| first_indexed | 2024-03-10T14:59:35Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-10T14:59:35Z |
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| spelling | doaj.art-2364da74cb714d6cb335fbd259aa76832023-11-20T20:18:22ZengMDPI AGBrain Sciences2076-34252020-11-01101183310.3390/brainsci10110833Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood DisordersSwati Maitra0Nitin Khandelwal1Scherazad Kootar2Pooja Sant3Salil S. Pathak4Sujatha Reddy5Annapoorna P. K.6Upadhyayula Suryanarayana Murty7Sumana Chakravarty8Arvind Kumar9Applied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaApplied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, IndiaApplied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, IndiaEpigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, IndiaDepression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and <i>ex vivo</i> DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of <i>Id2</i> (inhibitor of differentiation 2) and <i>Sox2</i> (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.https://www.mdpi.com/2076-3425/10/11/833jumonji domain-containing histone demethylasesDimethyloxallyl glycine (DMOG)epigenetic regulatorschromatin modificationsdentate gyrus (DG)neural stem or progenitor cells (NSCs/NPCs) |
| spellingShingle | Swati Maitra Nitin Khandelwal Scherazad Kootar Pooja Sant Salil S. Pathak Sujatha Reddy Annapoorna P. K. Upadhyayula Suryanarayana Murty Sumana Chakravarty Arvind Kumar Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders Brain Sciences jumonji domain-containing histone demethylases Dimethyloxallyl glycine (DMOG) epigenetic regulators chromatin modifications dentate gyrus (DG) neural stem or progenitor cells (NSCs/NPCs) |
| title | Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders |
| title_full | Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders |
| title_fullStr | Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders |
| title_full_unstemmed | Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders |
| title_short | Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders |
| title_sort | histone lysine demethylase jmjd2d kdm4d and family members mediate effects of chronic social defeat stress on mouse hippocampal neurogenesis and mood disorders |
| topic | jumonji domain-containing histone demethylases Dimethyloxallyl glycine (DMOG) epigenetic regulators chromatin modifications dentate gyrus (DG) neural stem or progenitor cells (NSCs/NPCs) |
| url | https://www.mdpi.com/2076-3425/10/11/833 |
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