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

持续的DNA损伤可阻断复制和转录，从而破坏细胞内稳态，从而损害发育并加速衰老。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。我们以前开发了一个C。elegans模型作为简单的后生动物系统，用于研究活体生物在发育和衰老过程中由DNA损伤引起的生理畸变。我们最近确定了一个特定的作用，表观遗传修饰，H3 K4 me 2，在恢复蛋白质生物合成和稳态的基因的表达后，转录阻断DNA损伤的修复。通过消耗H3 K4 me 2甲基转移酶和去甲基化酶来操纵H3 K4 me 2的沉积影响UV诱导的DNA损伤后的发育、生长和衰老。虽然未能存款这种特异性标记是有害的，但升高的H3 K4 me 2水平促进蛋白质生物合成的恢复，并随后促进发育生长和寿命。我们推测，一个特定的DNA修复依赖性组蛋白标记的沉积调节生物体的能力，通过调节蛋白质的生物合成和体内平衡的DNA损伤中生存。这种H3 K4 me 2沉积沿着开放阅读框架的作用使我们能够在DNA损伤、表观遗传学、转录延长和蛋白质稳态之间建立一种范式联系，这些都复杂地参与了衰老过程。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遗传毒性应激中维持生物体内平衡的机制基础。我们的目标是揭示MLL-COMPASS复合物的募集机制，该复合物将H3 K4 me 2标记沿着特定的开放阅读框架沉积，以及这与转录停滞和TC-NER的关系。我们希望了解H3 K4 me 2沉积如何调节转录阻断损伤去除后转录延长的恢复。最后，我们将利用C. elegans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。总之，我们的目标是揭示新的光染色质结构和基因表达的表观遗传维持调节的发展和衰老的生物体的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.