Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart

Harikrishnan K N; Jun Okabe; Prabhu Mathiyalagan; Abdul Waheed Khan; Sameer A Jadaan; Gulcan Sarila; Mark Ziemann; Ishant Khurana; Scott S Maxwell; Xiao-Jun Du; Assam El-Osta

doi:10.1016/j.isci.2019.06.031

Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart

iScience. 2019 Jul 26:17:288-301. doi: 10.1016/j.isci.2019.06.031. Epub 2019 Jun 27.

Affiliations

¹ Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia.
² Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia.
³ Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia.
⁴ Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR; University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark. Electronic address: sam.el-osta@monash.edu.

Abstract

In the heart, primary microRNA-208b (pri-miR-208b) and Myheart (Mhrt) are long non-coding RNAs (lncRNAs) encoded by the cardiac myosin heavy chain genes. Although preclinical studies have shown that lncRNAs regulate gene expression and are protective for pathological hypertrophy, the mechanism underlying sex-based differences remains poorly understood. In this study, we examined DNA- and RNA-methylation-dependent regulation of pri-miR-208b and Mhrt. Expression of pri-miR-208b is elevated in the left ventricle of the female heart. Despite indistinguishable DNA methylation between sexes, the interaction of MeCP2 on chromatin is subject to RNase digestion, highlighting that affinity of the methyl-CG reader is broader than previously thought. A specialized procedure to isolate RNA from soluble cardiac chromatin emphasizes sex-based affinity of an MeCP2 co-repressor complex with Rest and Hdac2. Sex-specific Mhrt methylation chromatinizes MeCP2 at the pri-miR-208b promoter and extends the functional relevance of default transcriptional suppression in the heart.

Keywords: Molecular Genetics; Molecular Mechanism of Gene Regulation; Molecular Physiology.