ArticleGenome biology2020
DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance.
Article in Genome biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 71 citations in OpenAlex.
- Whole-genome 5-hydroxymethylation profiling of human neurons for regulatory and biological insight.Epigenetics & chromatin · 2026Article
- Hypoxia Associated Integration of Epigenetic, Metabolic, and Immune Biomarkers in Blood and Urine for Early Colorectal Cancer Detection: A Multimarker Panel.Diagnostics (Basel, Switzerland) · 2026Article
- Systematic investigation of interindividual variation of DNA methylation in human whole blood.Genome biology · 2026Article
- BayesPI-FLY: a Bayesian neural network approach for inferring feature weighted TF-DNA interaction.Briefings in bioinformatics · 2026Article
- Hypoxic adaptation theory of cancer.Frontiers in cell and developmental biology · 2026Article
- Hypoxia regulates epithelial to mesenchymal transition-associated genes in human trophoblast cells by modulating DNA methylation.PloS one · 2026Article
- TET-mediated 5hmC in breast cancer: mechanism and clinical potential.Epigenetics · 2025Review
- Hypoxia-mediated regulation of mRNA metabolism: from transcription to stability.Cell communication and signaling : CCS · 2025Review
- Hypoxia-induced genome-wide DNA demethylation by DNMT3A and EMT of cancer cells.Cellular & molecular biology letters · 2025Article
- Epigenomic signatures of accelerated epigenetic aging are associated with congenital heart disease in newborns.BMC medical genomics · 2025Article
- HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.Cell · 2025Article
- Hypoxia-induced ATF3 escalates breast cancer invasion by increasing collagen deposition via P4HA1.Cell death & disease · 2025Article
- HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects.Cellular and molecular life sciences : CMLS · 2025Review
- NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment.Science advances · 2024Article
- Hypoxia-induced epigenetic regulation of miR-485-3p promotes stemness and chemoresistance in pancreatic ductal adenocarcinoma via SLC7A11-mediated ferroptosis.Cell death discovery · 2024Article
- Stratifying ICIs-responsive tumor microenvironment in HCC: from parsing out immune-hypoxic crosstalk to clinically applicable MRI-radiomics models.British journal of cancer · 2024Article
- IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions.International journal of molecular sciences · 2024Article
- Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia.Clinical epigenetics · 2023Review
- Identification of mammalian transcription factors that bind to inaccessible chromatin.Nucleic acids research · 2023Article
- Extracellular Succinate: A Physiological Messenger and a Pathological Trigger.International journal of molecular sciences · 2023Review
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Authors and funding
25 authors at 8 institutions in 6 countries.
Funding
Abstract
backgroundHypoxia 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.
resultsWe 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, control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumors with high immune checkpoint expression, but not in tumors with low immune checkpoint expression, where they would compromise tumor immunotolerance. In a low-immunogenic tumor model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumor growth.
conclusionsOur data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.