DNA M ethylation R epels B inding of HIF T ranscription F actors to M aintain T umour I mmunotolerance
DNA M ethylation R epels B inding of HIF T ranscription F actors to M aintain T umour I mmunotolerance
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. ResultsHere, 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 modelling, 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 tumours with high immune checkpoint expression, but not in tumours with low immune checkpoint expression, where they would compromise tumour immunotolerance. In a low-immunogenic tumour model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumour growth. ConclusionsOur data elucidate the mechanism underlying cell-type specific responses to hypoxia, and suggest DNA methylation and hypoxia to underlie tumour immunotolerance.
Minnoye Liesbeth、D?ˉanna Flora、Xiong Jieyi、Smedt Julie De、Bieniasz-Krzywiec Pawel、Schoonjans Luc、Matthews Jason、Lambrechts Diether、Qian Junbin、Borre Marie De、Simon Celeste、Thienpont Bernard、Carmeliet Peter、Savvides Savvas N.、Reik Wolf、Rastinejad Fraydoon、Chandra Vikas、Dyck Laurien Van、Khorasanizadeh Sepideh、Zhao Hui、Berrens Rebecca V.、Amorim Ricardo、Mazzone Massimiliano
Center for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsLaboratory of Dermatology, Department of OncologyCenter for Cancer Biology||Laboratory of Molecular Oncology and Angiogenesis, Department of OncologyCenter for Cancer Biology||State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, Sun Yat-Sen University||Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer InstituteInstitute of Basic Medical Sciences, University of OsloCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsLaboratory for Functional Epigenetics, Department of Human GeneticsAbramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania||Department of Cell and Developmental Biology, Perelman School of Medicine, University of PennsylvaniaCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human Genetics||Laboratory for Functional Epigenetics, Department of Human GeneticsCenter for Cancer Biology||State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, Sun Yat-Sen University||Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer InstituteUnit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University||VIB Center for Inflammation ResearchEpigenetics Programme, Babraham Institute||Centre for Trophoblast Research, University of Cambridge||Wellcome Trust Sanger Institute||Department of Physiology, Development and Neuroscience, University of CambridgeTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford||Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and AgeingTarget Discovery Institute, Nuffield Department of Medicine, University of OxfordCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsTarget Discovery Institute, Nuffield Department of Medicine, University of OxfordCenter for Cancer Biology||Laboratory of Translational Genetics, Department of Human GeneticsEpigenetics Programme, Babraham Institute||University of Cambridge, The Old SchoolsCenter for Cancer Biology||Laboratory of Molecular Oncology and Angiogenesis, Department of OncologyCenter for Cancer Biology||Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology
基础医学分子生物学肿瘤学
DNA methylationhypoxiaHIFcryptic transcriptsimmunotherapycancertranscription factor binding
Minnoye Liesbeth,D?ˉanna Flora,Xiong Jieyi,Smedt Julie De,Bieniasz-Krzywiec Pawel,Schoonjans Luc,Matthews Jason,Lambrechts Diether,Qian Junbin,Borre Marie De,Simon Celeste,Thienpont Bernard,Carmeliet Peter,Savvides Savvas N.,Reik Wolf,Rastinejad Fraydoon,Chandra Vikas,Dyck Laurien Van,Khorasanizadeh Sepideh,Zhao Hui,Berrens Rebecca V.,Amorim Ricardo,Mazzone Massimiliano.DNA M ethylation R epels B inding of HIF T ranscription F actors to M aintain T umour I mmunotolerance[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.02.07.931071.点此复制
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