dc.contributor.advisor | Williams, Christopher S. | |
dc.creator | Brown, Rachel Elizabeth | |
dc.date.accessioned | 2022-09-21T17:44:53Z | |
dc.date.created | 2022-08 | |
dc.date.issued | 2022-07-18 | |
dc.date.submitted | August 2022 | |
dc.identifier.uri | http://hdl.handle.net/1803/17729 | |
dc.description.abstract | Aberrant epithelial differentiation and regeneration contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium (DSS)-induced colitis. Transcriptomic analyses implicated increased E box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we established that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared to unaffected controls. Finally, attenuation of MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Overall, we demonstrated novel, context-specific roles for MTG16 in colonic epithelial lineage allocation and protection from colitis that depend on its repression of E protein-mediated transcription. Future directions include mechanistic biochemical studies to validate MTG16 protein binding partners and gene targets and further investigation of the context-specific roles of myeloid translocation genes in multiple biological contexts. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | Differentiation | |
dc.subject | lineage allocation | |
dc.subject | epithelial regeneration | |
dc.subject | inflammatory bowel disease | |
dc.subject | colitis-associated cancer | |
dc.subject | MTG16 | |
dc.title | Myeloid translocation genes in intestinal and colonic epithelial differentiation, regeneration, and tumorigenesis | |
dc.type | Thesis | |
dc.date.updated | 2022-09-21T17:44:53Z | |
dc.type.material | text | |
thesis.degree.name | PhD | |
thesis.degree.level | Doctoral | |
thesis.degree.discipline | Cancer Biology | |
thesis.degree.grantor | Vanderbilt University Graduate School | |
local.embargo.terms | 2024-08-01 | |
local.embargo.lift | 2024-08-01 | |
dc.creator.orcid | 0000-0002-3095-5903 | |
dc.contributor.committeeChair | Fingleton, Barbara M. | |