Transcriptional Corepressor MTG16 Regulates Small Intestinal Crypt Proliferation and Crypt Regeneration After Radiation-Induced Injury
National Institutes of Health, National Center for Advancing Translational Sciences
1F30-DK-103498, K08-DK-080221, P30-DK-058404, P50-CA-095103, R01-DK-099204, T32-GM-07347, UL1TR000445
Department of Biology
Myeloidtranslocation genes (MTGs) are transcriptional corepressorsimplicated in development, malignancy, differentiation, and stem cellfunction. While MTG16 loss renders mice sensitive to chemicalcolitis, the role of MTG16 in the small intestine is unknown. Histologicalexamination revealed that Mtg16-/- mice have increasedenterocyte proliferation and goblet cell deficiency. After exposure toradiation, Mtg16-/- mice exhibited increased crypt viability anddecreased apoptosis compared with wild-type (WT) mice. Flow cytometricand immunofluorescence analysis of intestinal epithelial cellsfor phospho-histone H2A.X also indicated decreased DNA damageand apoptosis in Mtg16-/- intestines. To determine if Mtg16 deletionaffected epithelial cells in a cell-autonomous fashion, intestinal cryptswere isolated from Mtg16-/- mice. Mtg16-/-and WT intestinalcrypts showed similar enterosphere forming efficiencies when culturedin the presence of EGF, Noggin, and R-spondin. However, whenMtg16-/- crypts were cultured in the presence of Wnt3a, theydemonstrated higher enterosphere forming efficiencies and delayedprogression to mature enteroids. Mtg16-/- intestinal crypts isolatedfrom irradiated mice exhibited increased survival compared with WTintestinal crypts. Interestingly, Mtg16 expression was reduced in astem cell-enriched population at the time of crypt regeneration. Thisis consistent with MTG16 negatively regulating regeneration in vivo.Taken together, our data demonstrate that MTG16 loss promotesradioresistance and impacts intestinal stem cell function, possibly dueto shifting cellular response away from DNA damage-induced apoptosisand towards DNA repair after injury.
Poindexter Toliver, Shenika V.; Reddy, V. K.; Mittal, M. K.; Williams, A. M.; Washington, M. K.; Harris, E.; Mah, A.; and Hiebert, S. W., "Transcriptional Corepressor MTG16 Regulates Small Intestinal Crypt Proliferation and Crypt Regeneration After Radiation-Induced Injury" (2015). Faculty and Staff Publications. 188.