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

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

  • Sci Adv. 2024 Jan 12;10(2):eadh9871. doi: 10.1126/sciadv.adh9871.
Zhensheng Hu 1,  Yunkun Lu 1,  Jie Cao 2 3,  Lianyu Lin 1,  Xi Chen 1,  Ziyu Zhou 1,  Jiaqi Pu 1 4,  Guo Chen 1,  Xiaojie Ma 1,  Qian Deng 1,  Yan Jin 1,  Liling Jiang 1,  Yuhan Li 1,  Tengwei Li 2,  Jianzhao Liu 2 3,  Saiyong Zhu 1
Affiliations

Affiliations

  • 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.
PMID: 38215194 DOI: 10.1126/sciadv.adh9871
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 N4-acetylcytidine (ac4C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac4C 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-ac4C-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.

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