Tumour hypoxia causes DNA hypermethylation by reducing TET activity

Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumour suppressor gene promoters are markedly more methylated in hypoxic tumour tissue, independent of proliferation, stromal cell infiltration and tumour characteristics. Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylatio

Plant Science Data Integration, from Building Community Standards to Defining a Consistent Data Lifecycle

FAIR (Findable, Accessible, Interoperable, Reusable) data principles for plant research build upon experience from other life science domains such as genomics. But plant specificities, e.g. plant-environment interactions or phenotypes, require tailored solutions. Major global players have joined forces to answer that challenge with the Minimal Information About a Plant Phenotyping Experiment (MIAPPE, www.miappe.org) that handles general metadata organization and its companion web service API, the Breeding API (www.brapi.org). Both rely on two established data standards, the MultiCrop Passport Descriptors (MCPD) for identification of plant genetic resources and the Crop Ontology (www.cropontology.org) for trait documentation. Researcher communities’ coordination and collaborative approaches have enabled the success and adoption of MIAPPE and led to a general data lifecycle description by ELIXIR Plant Sciences Community to identify gaps and needed developments. A priority has been placed on addressing the “first mile” of data publishing, i.e. the gathering and documentation of data by the researcher, which enables relevant data findability and reusability. Here we describe the existing ecosystem of tools and standards for plant scientists as well as their history, including their convergence through the use of MIAPPE for describing genotyping datasets

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

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