The roles of DNA methylation and hydroxymethylation at short interspersed nuclear elements in the hypothalamic arcuate nucleus during puberty

Yihang Shen; Hongchao Zhao; Lei Zhang; Yanping Hu; Li Cai; Jun Li; Shasha Zhou

doi:10.1016/j.omtn.2021.07.006

The roles of DNA methylation and hydroxymethylation at short interspersed nuclear elements in the hypothalamic arcuate nucleus during puberty

Mol Ther Nucleic Acids. 2021 Jul 21:26:242-252. doi: 10.1016/j.omtn.2021.07.006. eCollection 2021 Dec 3.

Authors

Yihang Shen¹, Hongchao Zhao², Lei Zhang³, Yanping Hu⁴, Li Cai⁵, Jun Li⁶, Shasha Zhou⁷

Affiliations

¹ Department of Central Laboratory, Suzhou Ninth People's Hospital, Suzhou, Jiangsu 215200, China.
² Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450002, China.
³ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
⁴ Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, China.
⁵ Department of Neurology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
⁶ Neonatology Department, Suzhou Ninth People's Hospital, Suzhou, Jiangsu 215200, China.
⁷ Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.

Abstract

Puberty is the gateway to adult reproductive competence, encompassing a suite of complex, integrative, and coordinated changes in neuroendocrine functions. However, the regulatory mechanisms of transcriptional reprogramming in the arcuate nucleus (ARC) during onset of puberty are still not fully understood. To understand the role of epigenetics in regulating gene expression, mouse hypothalamic ARCs were isolated at 4 and 8 weeks, and the transcriptome, DNA hydroxymethylation, DNA methylation, and chromatin accessibility were assessed via RNA sequencing (RNA-seq), reduced representation bisulfite sequencing (RRBS-seq), reduced representation hydroxymethylation profiling (RRHP)-seq, and assay for transposase-accessible chromatin (ATAC-seq), respectively. The overall DNA hydroxymethylation and DNA methylation changes in retroelements (REs) were associated with gene expression modeling for puberty in the ARC. We focused on analyzing DNA hydroxymethylation and DNA methylation at two short interspersed nuclear elements (SINEs) located on the promoter of the 5-hydroxytryptamine receptor 6 (Htr6) gene and the enhancer of the KISS-1 metastasis suppressor (Kiss1) gene and investigated their regulatory roles in gene expression. Our data uncovered a novel epigenetic mechanism by which SINEs regulate gene expression during puberty.

Keywords: 5-hydroxytryptamine receptor 6; DNA hydroxymethylation; DNA methylation; KISS-1 metastasis suppressor; Nuclear receptor subfamily 5 group A member 2; arcuate nucleus; enhancer; puberty; retroelement; short interspersed nuclear elements.