Linking chromatin acylation mark-defined proteome and genome in living cells

Fangfei Qin; Boyuan Li; Hui Wang; Sihui Ma; Jiaofeng Li; Shanglin Liu; Linghao Kong; Huangtao Zheng; Rongfeng Zhu; Yu Han; Mingdong Yang; Kai Li; Xiong Ji; Peng R Chen

doi:10.1016/j.cell.2023.02.007

Linking chromatin acylation mark-defined proteome and genome in living cells

Cell. 2023 Mar 2;186(5):1066-1085.e36. doi: 10.1016/j.cell.2023.02.007.

Authors

Fangfei Qin¹, Boyuan Li², Hui Wang², Sihui Ma³, Jiaofeng Li⁴, Shanglin Liu⁴, Linghao Kong³, Huangtao Zheng³, Rongfeng Zhu³, Yu Han⁴, Mingdong Yang⁴, Kai Li⁵, Xiong Ji⁶, Peng R Chen⁷

Affiliations

¹ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Shenzhen Bay Laboratory, Shenzhen 518055, China. Electronic address: fangfeiqin@pku.edu.cn.
² Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China.
³ Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
⁴ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
⁵ Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
⁶ Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: xiongji@pku.edu.cn.
⁷ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy of Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Shenzhen Bay Laboratory, Shenzhen 518055, China. Electronic address: pengchen@pku.edu.cn.

PMID: 36868209
DOI: 10.1016/j.cell.2023.02.007

Abstract

A generalizable strategy with programmable site specificity for in situ profiling of histone modifications on unperturbed chromatin remains highly desirable but challenging. We herein developed a single-site-resolved multi-omics (SiTomics) strategy for systematic mapping of dynamic modifications and subsequent profiling of chromatinized proteome and genome defined by specific chromatin acylations in living cells. By leveraging the genetic code expansion strategy, our SiTomics toolkit revealed distinct crotonylation (e.g., H3K56cr) and β-hydroxybutyrylation (e.g., H3K56bhb) upon short chain fatty acids stimulation and established linkages for chromatin acylation mark-defined proteome, genome, and functions. This led to the identification of GLYR1 as a distinct interacting protein in modulating H3K56cr's gene body localization as well as the discovery of an elevated super-enhancer repertoire underlying bhb-mediated chromatin modulations. SiTomics offers a platform technology for elucidating the "metabolites-modification-regulation" axis, which is widely applicable for multi-omics profiling and functional dissection of modifications beyond acylations and proteins beyond histones.

Keywords: chromatin; crotonylation; gene regulation; genetic code expansion; histone mark; metabolites; multi-omics; post-translational modification; super-enhancer; β-hydroxybutyrylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acylation
Cell Survival
Chromatin*
Chromosome Mapping
Histones
Proteome*

Substances

Chromatin
Histones
Proteome