title: Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Shenika V
authors.initials: SV
authors.lastname: Poindexter
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Vishruth K
authors.initials: VK
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee;
authors.forename: Mukul K
authors.initials: MK
authors.lastname: Mittal
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Williams
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harris
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Amanda
authors.initials: A
authors.lastname: Mah
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.affiliation: Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee;
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: P Kay
authors.initials: PK
authors.lastname: Lund
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; and christopher.s.williams@vanderbilt.edu.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004249:DNA Damage; D005260:Female; D005720:Gamma Rays; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011836:Radiation Tolerance; D012038:Regeneration / Q000187:drug effects; D012097:Repressor Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060509:Wnt3A Protein / Q000494:pharmacology
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D060509:Wnt3A Protein; C117411:Cbfa2t3 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: MTG16; enteroid; intestinal crypt regeneration; radiation enteritis; transcriptional corepressors