Fang Yao1, Peng Yu1, Yue Li2, Xinli Yuan1, Zheng Li1, Tao Zhang3, Fei Liu1, Yingbao Wang1,4, Yin Wang, Dandan Li1, Baihui Ma4, Chang Shu5, Wei Kong4, Bingying Zhou1, Li Wang1. 1. State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases (F.Y., P.Y., X.Y., Z.L., F.L., Y.W., D.L., B.Z., L.W.), Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing. 2. Department of Cardiac Surgery, Air Force General Hospital of People's Liberation Army, Beijing, China (Y.L.). 3. Department of Vascular Surgery, Peking University People's Hospital, Beijing, China (T.Z.). 4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China (Y.W., B.M., W.K.). 5. Department of Cardiovascular Surgery (C.S.), Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
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.
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.
Authors: Mingjun Liu; Cristina Espinosa-Diez; Sidney Mahan; Mingyuan Du; Anh T Nguyen; Scott Hahn; Raja Chakraborty; Adam C Straub; Kathleen A Martin; Gary K Owens; Delphine Gomez Journal: Dev Cell Date: 2021-09-27 Impact factor: 13.417