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

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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.
Funding Information
  • National Science and Technology Council (MOST 108–2321-B-182A-005, MOST 109–2326-B-182A-002, MOST 110–2326-B-182A-004, MOST 111–2326-B-182A-002, NSTC 112–2326-B-182A-004, NSTC 113–2320-B-182A-007)
  • Chang Gung Memorial Hospital (OMRPG3I0011, OMRPG3I0012, OMRPG3I0013, NMRPG3J0671, NMRPG3J0672, NMRPG3J0673, CORPG3J0231, CORPG3J0232)
  • China Medical University
  • Ministry of Education

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