N -acetyltransferase NAT10 controls cell fates via connecting mRNA cytidine acetylation to chromatin signaling

Author:

Hu Zhensheng1ORCID,Lu Yunkun1ORCID,Cao Jie23ORCID,Lin Lianyu1ORCID,Chen Xi1,Zhou Ziyu1ORCID,Pu Jiaqi14,Chen Guo1,Ma Xiaojie1ORCID,Deng Qian1,Jin Yan1,Jiang Liling1,Li Yuhan1,Li Tengwei2,Liu Jianzhao23ORCID,Zhu Saiyong1ORCID

Affiliation:

1. Life Sciences Institute, The Second Affiliated Hospital and School of Medicine, The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.

2. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China.

3. Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.

4. The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Abstract

Cell fate transition involves dynamic changes of gene regulatory network and chromatin landscape, requiring multiple levels of regulation, yet the cross-talk between epitranscriptomic modification and chromatin signaling remains largely unknown. Here, we uncover that suppression of N -acetyltransferase 10 (NAT10), the writer for mRNA N 4 -acetylcytidine (ac 4 C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac 4 C modification regulates the protein levels of a subset of its targets, which are strongly enriched for fate-instructive chromatin regulators, and among them, histone chaperone ANP32B is experimentally verified and functionally relevant. Furthermore, NAT10-ac 4 C-ANP32B axis can modulate the chromatin landscape of their downstream genes (e.g., key regulators of Wnt and TGFβ pathways). Collectively, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a critical layer of epitranscriptomic modulation and uncover a previously unrecognized, direct cross-talk between epitranscriptomic modification and chromatin signaling during cell fate transitions.

Publisher

American Association for the Advancement of Science (AAAS)

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