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

持续的DNA损伤可以阻止复制和转录，从而破坏细胞的动态平衡，从而损害发育和加速衰老。在发育和衰老的生物体中，DNA损伤的病理后果的分子机制还不完全清楚。我们已经开发了一个线虫模型，作为简单的后生动物系统，用于研究活生物体在发育和衰老过程中DNA损伤引起的生理异常。我们最近发现了表观遗传修饰H3K4me2在转录阻断DNA损伤修复后恢复蛋白质生物合成和动态平衡相关基因表达方面的特定作用。通过消耗H3K4me2甲基转移酶和去甲基酶来控制H3K4me2的沉积，影响紫外线诱导的DNA损伤的发育、生长和衰老。虽然未能沉积这种特定的标记是有害的，但H3K4me2水平的升高有助于蛋白质生物合成的恢复，并随后促进发育生长和寿命。我们假设，特定的DNA修复依赖的组蛋白标记的沉积通过调节蛋白质的生物合成和内稳态来调节生物体在DNA损伤中生存的能力。H3K4me2沿着开放阅读框架的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一种聚合关系，这些都与衰老过程复杂相关。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。我们将阐明表观遗传修饰如何在基因毒性压力下维持机体的动态平衡的机制基础。我们的目标是揭示沿着特定的开放阅读框架沉积H3K4me2标记的MLL-COMPASS复合体的招募机制，以及这与转录停滞和TC-NER的关系。我们希望了解H3K4me2沉积如何调节转录阻断病变移除后转录延伸的恢复。最后，我们将利用线虫强大的遗传学来研究与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，我们的目标是阐明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有机体对DNA损伤的生理适应。

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.