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

(2020) GENOME BIOLOGY. 21(1).
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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, 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. Conclusions Our data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.
Keywords
GENE-EXPRESSION, CANCER, HIF, ELEMENTS, CELLS, TET, REGIONS, SYSTEM, OUTPUT, SITES, DNA methylation, Hypoxia, HIF, Cryptic transcripts, Immunotherapy, Cancer, Transcription factor binding

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MLA
D’Anna, Flora, et al. “DNA Methylation Repels Binding of Hypoxia-Inducible Transcription Factors to Maintain Tumor Immunotolerance.” GENOME BIOLOGY, vol. 21, no. 1, 2020, doi:10.1186/s13059-020-02087-z.
APA
D’Anna, F., Van Dyck, L., Xiong, J., Zhao, H., Berrens, Rebecca, V., Qian, J., … Lambrechts, D. (2020). DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. GENOME BIOLOGY, 21(1). https://doi.org/10.1186/s13059-020-02087-z
Chicago author-date
D’Anna, Flora, Laurien Van Dyck, Jieyi Xiong, Hui Zhao, V Berrens, Rebecca, Junbin Qian, Pawel Bieniasz-Krzywiec, et al. 2020. “DNA Methylation Repels Binding of Hypoxia-Inducible Transcription Factors to Maintain Tumor Immunotolerance.” GENOME BIOLOGY 21 (1). https://doi.org/10.1186/s13059-020-02087-z.
Chicago author-date (all authors)
D’Anna, Flora, Laurien Van Dyck, Jieyi Xiong, Hui Zhao, V Berrens, Rebecca, Junbin Qian, Pawel Bieniasz-Krzywiec, Vikas Chandra, Luc Schoonjans, Jason Matthews, Julie De Smedt, Liesbeth Minnoye, Ricardo Amorim, Sepideh Khorasanizadeh, Qian Yu, Liyun Zhao, Marie De Borre, Savvas Savvides, M. Celeste Simon, Peter Carmeliet, Wolf Reik, Fraydoon Rastinejad, Massimiliano Mazzone, Bernard Thienpont, and Diether Lambrechts. 2020. “DNA Methylation Repels Binding of Hypoxia-Inducible Transcription Factors to Maintain Tumor Immunotolerance.” GENOME BIOLOGY 21 (1). doi:10.1186/s13059-020-02087-z.
Vancouver
1.
D’Anna F, Van Dyck L, Xiong J, Zhao H, Berrens, Rebecca V, Qian J, et al. DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. GENOME BIOLOGY. 2020;21(1).
IEEE
[1]
F. D’Anna et al., “DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance,” GENOME BIOLOGY, vol. 21, no. 1, 2020.
@article{8672154,
  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, 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. Conclusions Our data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.},
  articleno    = {182},
  author       = {D'Anna, Flora and Van Dyck, Laurien and Xiong, Jieyi and Zhao, Hui and Berrens, Rebecca, V and Qian, Junbin and Bieniasz-Krzywiec, Pawel and Chandra, Vikas and Schoonjans, Luc and Matthews, Jason and De Smedt, Julie and Minnoye, Liesbeth and Amorim, Ricardo and Khorasanizadeh, Sepideh and Yu, Qian and Zhao, Liyun and De Borre, Marie and Savvides, Savvas and Simon, M. Celeste and Carmeliet, Peter and Reik, Wolf and Rastinejad, Fraydoon and Mazzone, Massimiliano and Thienpont, Bernard and Lambrechts, Diether},
  issn         = {1474-760X},
  journal      = {GENOME BIOLOGY},
  keywords     = {GENE-EXPRESSION,CANCER,HIF,ELEMENTS,CELLS,TET,REGIONS,SYSTEM,OUTPUT,SITES,DNA methylation,Hypoxia,HIF,Cryptic transcripts,Immunotherapy,Cancer,Transcription factor binding},
  language     = {eng},
  number       = {1},
  pages        = {36},
  title        = {DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance},
  url          = {http://dx.doi.org/10.1186/s13059-020-02087-z},
  volume       = {21},
  year         = {2020},
}

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