Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response

Nature Communications

Keren Zhang¹  Qiushi Chen¹  Yan Ren¹  Yimin Liu²  Tongyi Dou²  Jianing Zhang²  Xinya Hao²  Wenli Li²  Nana Zhang²  Yu Cao²  Kun Li²  Xueqin Xie²  Yubo Liu² 

[1]Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China

[2]School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China

DOI  :  10.1038/s41467-020-19579-y

来源: Springer

【 摘 要 】

O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear respiratory factor 1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress.

【 授权许可】

CC BY