Interrogation of the interplay between DNA N6-methyladenosine (6mA) and hypoxia-induced chromatin accessibility by a randomized empirical model (EnrichShuf)

Joseph Chieh Yu Lai, Kai Wen Hsu, Kou Juey Wu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

Abstract

N6-Methyladenosine(6mA) is an epigenetic mark in eukaryotes regulating development, stress response and tumor progression. METTL4 has been reported as a 6mA methyltransferase induced by hypoxia. The detection and annotation of 6mA signals in mammalian cells have been hampered by the techniques and analytical methods developed so far. Here we developed a 6mA-ChIP-exo-5.1-seq to improve the sensitivity of detecting 6mAs in human cell lines. Furthermore, an EnrichShuf analysis tool for comprehensively comparing 6mA-ChIP-exo-5.1-seq, ATAC-seq, ChIP-seq and RNA-seq has been developed to annotate the functional relevance of 6mA in relation to chromatin accessibility and histone marks. Using a hypoxia-induced 6mA induction system as a model, we showed that hypoxic 6mA signals positively correlated with accessible chromatin regions. These 6mA signals correlate with their regulation by METTL4 under hypoxia, consistent with previous results. 6mAs also co-exist with H3K4me1, a histone mark for enhancers. Further analysis of enhancers using an ABC (active-by-contact) model shows that hypoxia-inducible factor-1α-induced H3K4me3 surrounds the 6mA/H3K4me1 site to augment active enhancers. These results suggest that correlation between 6mA and accessible chromatin regions plays a significant role in enhancer-promoter interactions during hypoxia-induced gene expression.

Original languageEnglish
Pages (from-to)13605-13624
Number of pages20
JournalNucleic Acids Research
Volume52
Issue number22
DOIs
StatePublished - 11 12 2024

Bibliographical note

© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.

Keywords

  • Adenosine/analogs & derivatives
  • Humans
  • Chromatin/metabolism
  • Methyltransferases/metabolism
  • Cell Hypoxia/genetics
  • Histones/metabolism
  • DNA Methylation
  • DNA/metabolism
  • Chromatin Immunoprecipitation Sequencing
  • Epigenesis, Genetic
  • Hypoxia/metabolism
  • Cell Line

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