Histone Variant H2A.Z Is Required for the Maintenance of Smooth Muscle Cell Identity as Revealed by Single-Cell Transcriptomics

Fang Yao, Peng Yu, Yue Li, Xinli Yuan, Zheng Li, Tao Zhang, Fei Liu, Yingbao Wang, Yin Wang, Dandan Li, Baihui Ma, Chang Shu, Wei Kong, Bingying Zhou, Li Wang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background: Histone variants endow chromatin with specific structures, and play essential roles in development and diseases. However, little is known about their roles in controlling cell identity in vascular diseases. Methods: Given the cell heterogeneity in atherosclerotic lesions, we applied single-cell RNA-Sequencing to analyze diseased human arteries, and identified histone variant H2A.Z as a key histone signature to maintain vascular smooth muscle cell (VSMC) identity. Results: We show that H2A.Z occupies genomic regions near VSMC marker genes, and its occupancy is decreased in VSMCs undergoing dedifferentiation. Mechanistically, H2A.Z occupancy preferentially promotes nucleosome turnover, and facilitates the recruitment of SMAD3 and MED1, thereby activating VSMC marker gene expression. In addition, H2A.Z expression is dramatically reduced at both mRNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescues injury-induced loss of VSMC identity and neointima formation. Conclusions: Together, our data introduce dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions, and imply H2A.Z as a potential intervention node for vascular diseases.

Original languageEnglish
Pages (from-to)2274-2288
Number of pages15
JournalCirculation
Volume138
Issue number20
DOIs
StatePublished - 13 Nov 2018
Externally publishedYes

Keywords

  • histones
  • smooth muscle cells
  • vascular diseases

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