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Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that\n                      <jats:italic>CBS<\/jats:italic>\n                      epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of\n                      <jats:italic>CBS<\/jats:italic>\n                      in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles,\n                      <jats:italic>CBS<\/jats:italic>\n                      loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H\n                      <jats:sub>2<\/jats:sub>\n                      S), with concomitant increase in NF-\u03baB activity. In a murine genetic model of\n                      <jats:italic>CBS<\/jats:italic>\n                      deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results implicate\n                      <jats:italic>CBS<\/jats:italic>\n                      as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H\n                      <jats:sub>2<\/jats:sub>\n                      S donors as a potential new therapy for\n                      <jats:italic>CBS<\/jats:italic>\n                      -silenced lesions.\n                    <\/jats:p>\n                  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PLoS Genet. 2009;5(10):e1000676. https:\/\/doi.org\/10.1371\/journal.pgen.1000676.","journal-title":"PLoS Genet"}],"updated-by":[{"DOI":"10.1186\/s13059-021-02405-z","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000}}],"container-title":["Genome Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13059-021-02375-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13059-021-02375-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13059-021-02375-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T20:25:57Z","timestamp":1627676757000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomebiology.biomedcentral.com\/articles\/10.1186\/s13059-021-02375-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":84,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2375"],"URL":"https:\/\/doi.org\/10.1186\/s13059-021-02375-2","relation":{},"ISSN":["1474-760X"],"issn-type":[{"value":"1474-760X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,1]]},"assertion":[{"value":"28 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1186\/s13059-021-02405-z","URL":"https:\/\/doi.org\/10.1186\/s13059-021-02405-z","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Primary GC patient samples for quantitative PCR validation were obtained from the SingHealth tissue repository with approval from the SingHealth Centralised IRB (SingHealth CIRB 2019\/2617) and signed patient informed consent, and complied with the Helsinki Declaration. <i>Tg-hCBS Cbs<\/i><sup>\u2212\/\u2212<\/sup> animal studies were reviewed and approved by the Fox Chase Cancer Center Institutional Animal Care and Review Board.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"167"}}