Hypoxia regulates allele-specific histone modification of the imprinted H19 gene

• Published in: Biochimica et biophysica acta. Gene regulatory mechanisms 2020-11, Vol.1863 (11), p.194643-194643, Article 194643
• Main Authors: Moon, Yunwon, Kim, Ingyum, Chang, Soojeong, Park, Bongju, Lee, Seongyeol, Yoo, Seongwook, Chae, Sehyun, Hwang, Daehee, Park, Hyunsung
• Format: Article
• Language: English
• Subjects: Alleles; Base Sequence; DNA Methylation; Gene Expression Regulation; Genomic Imprinting; H19; HIF-1α; Histone modification; Histones - metabolism; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Imprinted gene; Methylation; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Processing, Post-Translational; RNA, Long Noncoding - genetics; Sequence Analysis, DNA
• ISSN: 1874-9399; 1876-4320
• DOI: 10.1016/j.bbagrm.2020.194643

H19 is a maternally-expressed imprinted gene that encodes long non-coding RNA. Chromatin immunoprecipitation (ChIP)-sequencing analyses of human adipose-derived stem cells (hADSCs) showed that hypoxia induced trimethylation of 4th lysine residue of histone 3 (H3K4me3) in the H19 gene, among the 40 known human imprinted genes, to the greatest extent. We investigated whether hypoxia changed the DNA and histone methylation levels of the imprinted H19 gene in an allele-specific (AS) manner. Using AS primer sets for the human H19 gene, we conducted ChIP-quantitative polymerase chain reaction, which revealed that hypoxia increased the active histone marks, H3K4me3 and H3K9/14Ac, in one allele (named B allele) but not in the other allele (named A allele). In contrast, hypoxia did not change the H3K9me3 levels in either allele. Hypoxia-inducible factor 1 (HIF-1) directly bound to the H19 promoter only in the B allele. HIF-1α knock-down prevented the increase in the active histone modification and mRNA expression of the B allele under hypoxia, indicating that HIF-1α caused AS changes in the histone modification of the H19 gene. Long-term hypoxia did not change the AS DNA methylation throughout the cell cycle. Thus, hypoxia changed the histone modification of the active allele in an HIF-1α-dependent manner, without changing the imprinted status of the H19 gene. •Hypoxia increases H3K4me3 in only active allele of H19 imprinted gene in HIF-1α dependent manner.•Clioquinol, a HIF-1α activator also increases H3K4me3 in only active allele of H19 imprinted gene.•Hypoxia showed no effect on the allele-specific DNA methylation of the H19 promoter.