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Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore,<jats:italic>Crk\/Crkl<\/jats:italic>deficiency sensitizes MEFs to 2-deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk\/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk\/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls.<\/jats:p>","DOI":"10.26508\/lsa.201900635","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T18:35:14Z","timestamp":1581359714000},"page":"e201900635","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Essential role of the<i>Crk<\/i>family-dosage in DiGeorge-like anomaly and metabolic homeostasis"],"prefix":"10.26508","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1009-9302","authenticated-orcid":true,"given":"Akira","family":"Imamoto","sequence":"first","affiliation":[{"name":"The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sewon","family":"Ki","sequence":"additional","affiliation":[{"name":"RIKEN 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