American journal of physiology: Gastrointestinal and liver physiology, 2015-03, Vol.308 (6), p.G562-G571
2015
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- Autor(en) / Beteiligte
- Titel
- Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury
- Ist Teil von
- American journal of physiology: Gastrointestinal and liver physiology, 2015-03, Vol.308 (6), p.G562-G571
- Ort / Verlag
- United States: American Physiological Society
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Myeloid translocation genes (MTGs) are transcriptional corepressors implicated in development, malignancy, differentiation, and stem cell function. While MTG16 loss renders mice sensitive to chemical colitis, the role of MTG16 in the small intestine is unknown. Histological examination revealed that Mtg16(-/-) mice have increased enterocyte proliferation and goblet cell deficiency. After exposure to radiation, Mtg16(-/-) mice exhibited increased crypt viability and decreased apoptosis compared with wild-type (WT) mice. Flow cytometric and immunofluorescence analysis of intestinal epithelial cells for phospho-histone H2A.X also indicated decreased DNA damage and apoptosis in Mtg16(-/-) intestines. To determine if Mtg16 deletion affected epithelial cells in a cell-autonomous fashion, intestinal crypts were isolated from Mtg16(-/-) mice. Mtg16(-/-) and WT intestinal crypts showed similar enterosphere forming efficiencies when cultured in the presence of EGF, Noggin, and R-spondin. However, when Mtg16(-/-) crypts were cultured in the presence of Wnt3a, they demonstrated higher enterosphere forming efficiencies and delayed progression to mature enteroids. Mtg16(-/-) intestinal crypts isolated from irradiated mice exhibited increased survival compared with WT intestinal crypts. Interestingly, Mtg16 expression was reduced in a stem cell-enriched population at the time of crypt regeneration. This is consistent with MTG16 negatively regulating regeneration in vivo. Taken together, our data demonstrate that MTG16 loss promotes radioresistance and impacts intestinal stem cell function, possibly due to shifting cellular response away from DNA damage-induced apoptosis and towards DNA repair after injury.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0193-1857eISSN: 1522-1547DOI: 10.1152/ajpgi.00253.2014Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4360050
- Format
- –
- Schlagworte
- Animals, Apoptosis, Cell Proliferation - drug effects, Cell Survival, Digestive system, DNA Damage, DNA repair, Female, Flow cytometry, Gamma Rays, Gene Expression Regulation, Genes, Goblet Cells - metabolism, Goblet Cells - pathology, Histones - metabolism, Intestinal Mucosa - drug effects, Intestinal Mucosa - metabolism, Intestinal Mucosa - pathology, Intestine, Small - drug effects, Intestine, Small - metabolism, Intestine, Small - pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Mucosal Biology, Nuclear Proteins - deficiency, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Phenotype, Radiation, Radiation Injuries, Experimental - etiology, Radiation Injuries, Experimental - metabolism, Radiation Injuries, Experimental - pathology, Radiation Tolerance, Regeneration - drug effects, Repressor Proteins, Rodents, Signal Transduction, Stem Cells - metabolism, Stem Cells - pathology, Tissue Culture Techniques, Transcription factors, Transcription Factors - deficiency, Transcription Factors - genetics, Transcription Factors - metabolism, Wnt3A Protein - pharmacology