Epigenetic regulation of the cellular homeostasis amid transcription-blocking DNA damage during development and aging

发育和衰老过程中转录阻断 DNA 损伤中细胞稳态的表观遗传调控

• 批准号: 515756601
• 负责人: Professor Dr. Björn Schumacher
• 金额: --
• 依托单位: Institute for Genome Stability in Ageing and Disease
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515756601?language=en
• 关键词: Epigenetic; regulation; cellular; homeostasis; amid

Persistent DNA lesions can block replication and transcription thus disrupting cellular homeostasis consequently impairing development and accelerating aging. The molecular mechanism underlying the pathological consequences of DNA damage in the developing and aging organism are incompletely understood. We have previously developed a C. elegans model as simple metazoan system for investigating the physiological aberrations caused by DNA damage during development and the course of aging in a live organism. We recently identified a specific role of a epigenetic modification, H3K4me2, in the recovery of the expression of genes involved in protein biosynthesis and homeostasis following the repair of transcription-blocking DNA lesions. Manipulating the deposition of H3K4me2 through depleting H3K4me2 methyltransferases and demethylases influences the developmental growth and aging upon UV-induced DNA lesions. While a failure to deposit this specific mark was detrimental, elevated H3K4me2 levels facilitated the recovery of protein biosynthesis and subsequently promoting developmental growth and longevity. We hypothesize that the deposition of a specific DNA repair-dependent histone mark regulates the organism’s ability to survive amid DNA damage through the regulation of protein biosynthesis and homeostasis. The effects of this H3K4me2 deposition along open reading frames allows us to develop a paradigmatic connection between DNA damage, epigenetics, transcription elongation and protein homeostasis that are all intricately involved in the aging process. We will investigate how transcription-blocking DNA damage reshapes the epigenome and impacts developmental growth and aging. We will shed light on the mechanistic underpinnings how epigenetic modifications maintain organismal homeostasis amid genotoxic stress. We aim to uncover the mechanisms of the recruitment of the MLL-COMPASS complex that deposits the H3K4me2 marks along specific open reading frames and how this is related to transcription stalling and TC-NER. We wish to understand how the H3K4me2 deposition regulates the recovery of transcription elongation following transcription blocking lesion removal. Lastly, we will employ the powerful genetics of C. elegans to investigate how longevity associated regulators of protein biosynthesis and epigenetics impact the organism’s response to DNA damage. Taken together, we aim to shed new light on how epigenetic maintenance of chromatin structure and gene expression regulates the physiological adaptations of the developing and aging organism to DNA damage.

持续的DNA损伤可以阻断复制和转录，从而破坏细胞稳态，从而损害发育和加速衰老。在发育和衰老的生物体中，DNA损伤病理后果的分子机制尚不完全清楚。我们之前已经开发了秀丽隐杆线虫模型作为简单的后生动物系统，用于研究生物体在发育和衰老过程中DNA损伤引起的生理畸变。我们最近发现了表观遗传修饰H3K4me2在修复转录阻断DNA损伤后参与蛋白质生物合成和稳态的基因表达恢复中的特殊作用。通过消耗H3K4me2甲基转移酶和去甲基化酶来控制H3K4me2的沉积会影响紫外线诱导的DNA损伤后的发育生长和衰老。虽然这种特殊标记的沉积失败是有害的，但H3K4me2水平的升高促进了蛋白质生物合成的恢复，并随后促进了发育生长和寿命。我们假设特定的DNA修复依赖组蛋白标记的沉积通过调节蛋白质生物合成和体内平衡来调节生物体在DNA损伤中生存的能力。这种H3K4me2沿开放阅读框沉积的影响使我们能够在DNA损伤、表观遗传学、转录延伸和蛋白质稳态之间建立范式联系，这些都与衰老过程错综复杂地有关。我们将研究转录阻断DNA损伤如何重塑表观基因组并影响发育生长和衰老。我们将阐明在遗传毒性胁迫下表观遗传修饰如何维持生物体稳态的机制基础。我们的目标是揭示MLL-COMPASS复合体的招募机制，该复合体将H3K4me2标记沉积在特定的开放阅读框上，以及这与转录延迟和TC-NER之间的关系。我们希望了解H3K4me2沉积如何调节转录阻断病变去除后转录延伸的恢复。最后，我们将利用秀丽隐杆线虫强大的遗传学来研究长寿相关的蛋白质生物合成调节因子和表观遗传学如何影响生物体对DNA损伤的反应。综上所述，我们的目标是揭示染色质结构和基因表达的表观遗传维持如何调节发育和衰老生物体对DNA损伤的生理适应。