Maitra Swati, Khandelwal Nitin, Kootar Scherazad, Sant Pooja, Pathak Salil S, Reddy Sujatha, P K Annapoorna, Murty Upadhyayula Suryanarayana, Chakravarty Sumana, Kumar Arvind
Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India.
Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR-Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad, Telangana 500007, India.
Brain Sci. 2020 Nov 9;10(11):833. doi: 10.3390/brainsci10110833.
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 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 (inhibitor of differentiation 2) and (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.
抑郁症、焦虑症及相关情绪障碍是全球主要的精神疾病，慢性应激似乎是主要的潜在病因之一。由于对这些使人衰弱的疾病的病因病理学分子理解不完整，用于治疗这些疾病且无复发的疗法有限。除了已充分研究的遗传成分外，过去二十年的研究表明，多种表观遗传机制介导了慢性应激事件对神经回路的负面影响。这包括认知回路，其中动态海马齿状回（DG）神经发生在抑郁症及相关情感障碍中会受到影响。大多数这些表观遗传学研究都集中在几个组蛋白赖氨酸残基的乙酰化/去乙酰化和甲基化对神经基因表达的影响上。然而，对于这些赖氨酸残基的去甲基化在慢性应激诱导的神经发生变化导致行为改变中的作用，研究却很匮乏。在此，我们使用慢性社会挫败应激（CSDS）范式在C57BL/6小鼠中诱导抑郁和焦虑，并进行DG神经干细胞/祖细胞（NSCs/NPCs）培养，以展示组蛋白赖氨酸去甲基化酶（KDMs）的JMJD2/KDM4家族成员在介导应激诱导的DG神经发生变化和情绪障碍中的作用。该研究表明JMJD2D在DG神经发生中起关键作用。在从DG获得的NSCs/NPCs增殖和分化过程中，观察到JMJD2D在（分化抑制因子2）和（SRY盒转录因子2）启动子上的富集改变。这将影响抑制性表观遗传标记H3K9的去甲基化，从而激活或抑制这些以及可能其他参与调节DG NSCs/NPCs增殖和分化的基因。用JMJDs抑制剂二甲基草酰甘氨酸（DMOG）处理NSCs/NPCs培养物，导致其增殖能力减弱。此外，在小鼠中全身给予DMOG 10天，在没有任何应激暴露的情况下诱导出抑郁样和焦虑样表型。
