Research

Mechanisms of epigenetic modifications in chromatin homeostasis and human diseases

The proper transcriptional regulation of genetic DNA is intricately governed by dynamic chromatin structure and its related epigenetic modifications, which operate in a spatiotemporally controlled manner. This sophisticated regulatory network plays multifaceted roles in the development, differentiation, and metabolic processes of multicellular organisms. Dysregulation of epigenetic mechanisms is closely linked to various human diseases and aging. Our research study primarily focuses on elucidating the molecular mechanisms underlying epigenetic-mediated maintenance of homeostasis. We aim to address the following key questions:

1) how do epigenetic modifications detect and respond to DNA damage, repair processes, and DNA replication initiation? Moreover, how are these modifications accurately restored and transmitted once these processes conclude?

2) What mechanisms underlie the ability of epigenetic regulation to maintain cellular and organismal homeostasis? How does it retain memory of metabolic adaptations in response to nutrient fluctuations, whether deprivation or excess?

3) how can we identify novel molecular targets and develop new strategies for treating tumors or intervening in human aging processes?

Representative Publications

1. Duan H^#, Wang S^#, Shu WJ, Tong Y, Long HZ, Li G, Du HN*, Zhao MJ*. SETD3-mediated histidine methylation of MCM7 regulates DNA replication by facilitating chromatin loading of MCM. SCIENCE CHINA Life Sciences 2024 in press.

2. Chen R^#, Zhao MJ^#, Li YM, Liu AH, Wang RX, Mei YC, Chen X, Du HN*. Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair. SCIENCE CHINA Life Sciences 2024 in press.

3. Li YM^#, Mei YC^#, Liu AH, Wang RX, Chen R, Du HN*. Gcn5- and Bre1-mediated Set2 degradation promotes chronological aging of Saccharomyces cerevisiae. Cell Reports 2023 42(10):113186.

4. Geng Q^#, Kong YY^#, Li W^#, Zhang J^#, Ma H, Zhang Y, Da LT, Zhao Y*, Du HN*. Dynamic phosphorylation of G9a regulates its repressive activity on chromatin accessibility and mitotic progression. Adv Sci 2023 e2303224.

5. Zhao MJ^#, Yao X^#, Wei P#, Zhao C#, Cheng M, Zhang D, Xue W, He WT, Xue W, Zuo X, Jiang LL, Luo Z, Song J, Shu WJ, Yuan HY, Liang Y, Sun H, Zhou Y, Zhou Y, Zheng L, Hu HY, Wang J*, Du HN*. O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43's mRNA splicing activity. EMBO Rep 2021 22(6): e51649.

6. Zheng L^#, Shu WJ^#, Li YM, Mari M, Yan C, Wang D, Yin ZH, Jiang W, Zhou Y, Okamoto K, Reggiori F, Klionsky DJ, Song Z, Du HN*. The Paf1 complex transcriptionally regulates the mitochondrial-anchored protein Atg32 leading to activation of mitophagy. Autophagy 2020 8(6): 1366-1379.

7. Shu WJ, Chen R, Yin ZH, Li F, Zhang H, Du HN*. Rph1 coordinates transcription of ribosomal protein genes and ribosomal RNAs to control cell growth under nutrient stress conditions. Nucleic Acids Res 2020 48(15):8360-8373.

8. Li W^# Wang HY^#, Zhao X, Duan H, Cheng B, Liu Y, Zhao M, Shu W, Mei Y, Wen Z, Tang M, Guo L, Li G, Chen Q, Liu X, Du HN*. A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair. Sci Adv 2019 5(3): eaau7566.

9. Li F, Zheng LD, Chen X, Zhao X, Briggs SD, Du HN*. Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress. Nucleic Acids Res 2017, 45(9): 5183-5197.