DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance.

ABSTRACT:

Background

Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia.

Results

We report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modeling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid down by the differential expression and binding of other transcription factors under normoxia,

SUBMITTER: D'Anna F 

PROVIDER: S-EPMC7384226 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature