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Epigenetic regulation disorder is important in the onset and pathogenesis of inflammatory bowel disease (IBD). SETD2, a trimethyltransferase of histone H3K36, is frequently mutated in IBD samples with a high risk of developing colorectal cancer (CRC). However, functions of SETD2 in IBD and colitis-associated CRC remain largely undefined. Here, we found that SETD2 modulates oxidative stress to attenuate colonic inflammation and tumorigenesis in mice. SETD2 expression became decreased in IBD patients and dextran sodium sulfate (DSS)-induced colitic mice. Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, we found that Setd2 depletion resulted in excess reactive oxygen species (ROS) by directly down-regulating antioxidant genes, which led to defects in barrier integrity and subsequently inflammatory damage. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO intestinal epithelial cells (IECs) largely alleviated the overproductions of ROS and improved the cellular survival. Together, our findings highlight an epigenetic mechanism by which SETD2 modulates oxidative stress to regulate intestinal epithelial homeostasis and attenuate colonic inflammation and tumorigenesis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.
Pubmed ID: 34020310
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Collection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.
View all literature mentionsComputable knowledge regarding functions of genes and gene products. GO resources include biomedical ontologies that cover molecular domains of all life forms as well as extensive compilations of gene product annotations to these ontologies that provide largely species-neutral, comprehensive statements about what gene products do. Used to standardize representation of gene and gene product attributes across species and databases.
View all literature mentionsA portal to biomedical and genomic information. NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease.
View all literature mentionsSoftware tool that removes adapter sequences from DNA sequencing reads.
View all literature mentionsSoftware Java pipeline for trimming tasks for Illumina paired end and single ended data. Flexible Trimmer for Illumina Sequence Data. Pair aware preprocessing tool optimized for Illumina next generation sequencing data. Includes several processing steps for read trimming and filtering. Operating systems Unix/Linux, Mac OS, Windows.
View all literature mentionsA commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on March 17,2022. Genome databases for vertebrates and other eukaryotic species. Analysis and annotation maintained on current data.Distribution of analysis to other bioinformatics laboratories. Ensembl concentrates on vertebrate genomes, but other groups have adapted system for use with plant and fungal genomes (see Powered by Ensembl list on website).
View all literature mentionsQuality control software that perform checks on raw sequence data coming from high throughput sequencing pipelines. This software also provides a modular set of analyses which can give a quick impression of the quality of the data prior to further analysis.
View all literature mentionsGraph-based alignment of next generation sequencing reads to a population of genomes.
View all literature mentionsSoftware application for assembling of RNA-Seq alignments into potential transcripts. It enables improved reconstruction of a transcriptome from RNA-seq reads. This transcript assembling and quantification program is implemented in C++ .
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