Long non-coding RNA LHX1-DT regulates cardiomyocyte differentiation through H2A.Z-mediated LHX1 transcriptional activation

Qi Yu; Benzhi Cai; Yong Zhang; Juan Xu; Dongping Liu; Xiyang Zhang; Zhenbo Han; Yingying Ma; Lei Jiao; Manyu Gong; Xuewen Yang; Yanying Wang; Haodong Li; Lihua Sun; Yu Bian; Fan Yang; Lina Xuan; Haodi Wu; Baofeng Yang; Ying Zhang

doi:10.1016/j.isci.2023.108051

Long non-coding RNA LHX1-DT regulates cardiomyocyte differentiation through H2A.Z-mediated LHX1 transcriptional activation

iScience. 2023 Sep 25;26(11):108051. doi: 10.1016/j.isci.2023.108051. eCollection 2023 Nov 17.

Authors

Qi Yu^{1

2}, Benzhi Cai^{1

3}, Yong Zhang¹, Juan Xu⁴, Dongping Liu¹, Xiyang Zhang¹, Zhenbo Han⁵, Yingying Ma⁴, Lei Jiao¹, Manyu Gong¹, Xuewen Yang¹, Yanying Wang¹, Haodong Li¹, Lihua Sun¹, Yu Bian¹, Fan Yang¹, Lina Xuan¹, Haodi Wu², Baofeng Yang^{1

6}, Ying Zhang¹

Affiliations

¹ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China.
² Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
³ Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, Harbin 150081, China.
⁴ College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China.
⁵ Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, 909 S Wolcott Avenue, COMRB 4100, Chicago, IL 60612, USA.
⁶ Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences (2019RU070), Harbin 150086, China.

Abstract

Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they regulate early stage cardiomyocyte differentiation. In this study, we identified a specific lncRNA called LHX1-DT, which is transcribed from a bidirectional promoter of LIM Homeobox 1 (LHX1) gene. Our findings demonstrated that LHX1-DT is nuclear-localized and transiently elevated expression along with LHX1 during early differentiation of cardiomyocytes. The phenotype was rescued by overexpression of LHX1 into the LHX1-DT^-/- hESCs, indicating LHX1 is the downstream of LHX1-DT. Mechanistically, we discovered that LHX1-DT physically interacted with RNA/histone-binding protein PHF6 during mesoderm commitment and efficiently replaced conventional histone H2A with a histone variant H2A.Z at the promoter region of LHX1. In summary, our work uncovers a novel lncRNA, LHX1-DT, which plays a vital role in mediating the exchange of histone variants H2A.Z and H2A at the promoter region of LHX1.

Keywords: Molecular biology; Omics.