MTG16 Contributes to Colonic Epithelial Integrity in Experimental Colitis

Overview

Journal Gut

Specialty Gastroenterology

Date 2012 Jul 27

PMID 22833394

Citations 16

Authors

Christopher S Williams

Amber M Bradley

Rupesh Chaturvedi

Kshipra Singh

Maria B Piazuelo

Xi Chen

Elizabeth M McDonough

David A Schwartz

Caroline T Brown

Margaret M Allaman

Lori A Coburn

Sara N Horst

Dawn B Beaulieu

Yash A Choksi

Mary Kay Washington

Amanda D Williams

Melissa A Fisher

Sandra S Zinkel

Richard M Peek Jr

Keith T Wilson

Scott W Hiebert

Affiliations

Soon will be listed here.

Abstract

Objective: The myeloid translocation genes (MTGs) are transcriptional corepressors with both Mtg8(-/-) and Mtgr1(-/-) mice showing developmental and/or differentiation defects in the intestine. We sought to determine the role of MTG16 in intestinal integrity.

Methods: Baseline and stress induced colonic phenotypes were examined in Mtg16(-/-) mice. To unmask phenotypes, we treated Mtg16(-/-) mice with dextran sodium sulphate (DSS) or infected them with Citrobacter rodentium and the colons were examined for ulceration and for changes in proliferation, apoptosis and inflammation.

Results: Mtg16(-/-) mice have altered immune subsets, suggesting priming towards Th1 responses. Mtg16(-/-) mice developed increased weight loss, diarrhoea, mortality and histological colitis and there were increased innate (Gr1(+), F4/80(+), CD11c(+) and MHCII(+); CD11c(+)) and Th1 adaptive (CD4) immune cells in Mtg16(-/-) colons after DSS treatment. Additionally, there was increased apoptosis and a compensatory increased proliferation in Mtg16(-/-) colons. Compared with wild-type mice, Mtg16(-/-) mice exhibited increased colonic CD4;IFN-γ cells in vehicle-treated and DSS-treated mice. Adoptive transfer of wild-type marrow into Mtg16(-/-) recipients did not rescue the Mtg16(-/-) injury phenotype. Isolated colonic epithelial cells from DSS-treated Mtg16(-/-) mice exhibited increased KC (Cxcl1) mRNA expression when compared with wild-type mice. Mtg16(-/-) mice infected with C rodentium had more severe colitis and greater bacterial colonisation. Last, MTG16 mRNA levels were reduced in human ulcerative colitis versus normal colon tissues.

Conclusions: These observations indicate that MTG16 is critical for colonocyte survival and regeneration in response to intestinal injury and provide evidence that this transcriptional corepressor regulates inflammatory recruitment in response to injury.

Citing Articles

MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors.

Brown R, Jacobse J, Anant S, Blunt K, Chen B, Vega P JCI Insight. 2022; 7(10).

PMID: 35503250 PMC: 9220854. DOI: 10.1172/jci.insight.153045.

The Transcription Co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation Into Enterocyte vs Secretory Lineages.

Baulies A, Angelis N, Foglizzo V, Danielsen E, Patel H, Novellasdemunt L Gastroenterology. 2020; 159(4):1328-1341.e3.

PMID: 32553763 PMC: 7607384. DOI: 10.1053/j.gastro.2020.06.012.

Transcribed ultraconserved region (T-UCR) uc.261 expression is closely correlated with disease activity and intestinal permeability in Crohn's disease.

Qian X, Cai C, Li H, Lai L, Song D, Qiao Y Therap Adv Gastroenterol. 2019; 12:1756284819880733.

PMID: 31662792 PMC: 6796213. DOI: 10.1177/1756284819880733.

BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.

Choksi Y, K Reddy V, Singh K, Barrett C, Short S, Parang B Mucosal Immunol. 2018; 11(5):1363-1374.

PMID: 29907869 PMC: 6162166. DOI: 10.1038/s41385-018-0043-2.

Emerging Roles of MTG16 in Cell-Fate Control of Hematopoietic Stem Cells and Cancer.

Steinauer N, Guo C, Zhang J Stem Cells Int. 2018; 2017:6301385.

PMID: 29358956 PMC: 5735743. DOI: 10.1155/2017/6301385.

References

Qualls J, Tuna H, Kaplan A, Cohen D . Suppression of experimental colitis in mice by CD11c+ dendritic cells. Inflamm Bowel Dis. 2008; 15(2):236-47. DOI: 10.1002/ibd.20733. View

Mashimo H, Wu D, Podolsky D, Fishman M . Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996; 274(5285):262-5. DOI: 10.1126/science.274.5285.262. View

Davis J, Williams B, Herron J, Galiano F, Meyers S . ETO-2, a new member of the ETO-family of nuclear proteins. Oncogene. 1999; 18(6):1375-83. DOI: 10.1038/sj.onc.1202412. View

Edelblum K, Washington M, Koyama T, Robine S, Baccarini M, Polk D . Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology. 2008; 135(2):539-51. PMC: 2640938. DOI: 10.1053/j.gastro.2008.04.025. View

Amann J, Chyla B, Ellis T, Martinez A, Moore A, Franklin J . Mtgr1 is a transcriptional corepressor that is required for maintenance of the secretory cell lineage in the small intestine. Mol Cell Biol. 2005; 25(21):9576-85. PMC: 1265807. DOI: 10.1128/MCB.25.21.9576-9585.2005. View

Moore A, Amann J, Williams C, Tahinci E, Farmer T, Martinez J . Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription. Mol Cell Biol. 2007; 28(3):977-87. PMC: 2223385. DOI: 10.1128/MCB.01242-07. View

Hartupee J, Liu C, Novotny M, Li X, Hamilton T . IL-17 enhances chemokine gene expression through mRNA stabilization. J Immunol. 2007; 179(6):4135-41. DOI: 10.4049/jimmunol.179.6.4135. View

Mizoguchi E, Xavier R, Reinecker H, Uchino H, Bhan A, Podolsky D . Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology. 2003; 125(1):148-61. DOI: 10.1016/s0016-5085(03)00665-6. View

Calabi F, Cilli V . CBFA2T1, a gene rearranged in human leukemia, is a member of a multigene family. Genomics. 1998; 52(3):332-41. DOI: 10.1006/geno.1998.5429. View

10.

Mangan P, Harrington L, OQuinn D, Helms W, Bullard D, Elson C . Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006; 441(7090):231-4. DOI: 10.1038/nature04754. View

11.

Fukata M, Chen A, Klepper A, Krishnareddy S, Vamadevan A, Thomas L . Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Gastroenterology. 2006; 131(3):862-77. PMC: 2169292. DOI: 10.1053/j.gastro.2006.06.017. View

12.

Poritz L, Garver K, Green C, Fitzpatrick L, Ruggiero F, Koltun W . Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J Surg Res. 2007; 140(1):12-9. DOI: 10.1016/j.jss.2006.07.050. View

13.

Kitajima S, Takuma S, Morimoto M . Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium. Exp Anim. 1999; 48(3):137-43. DOI: 10.1538/expanim.48.137. View

14.

Yamagata T, Maki K, Mitani K . Runx1/AML1 in normal and abnormal hematopoiesis. Int J Hematol. 2005; 82(1):1-8. DOI: 10.1532/IJH97.05075. View

15.

Kitajima S, Takuma S, Morimoto M . Tissue distribution of dextran sulfate sodium (DSS) in the acute phase of murine DSS-induced colitis. J Vet Med Sci. 1999; 61(1):67-70. DOI: 10.1292/jvms.61.67. View

16.

Watanabe N, Ikuta K, Okazaki K, Nakase H, Tabata Y, Matsuura M . Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice. Dig Dis Sci. 2003; 48(2):408-14. DOI: 10.1023/a:1021960401290. View

17.

Elson C, Cong Y, McCracken V, Dimmitt R, Lorenz R, Weaver C . Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005; 206:260-76. DOI: 10.1111/j.0105-2896.2005.00291.x. View

18.

Singh K, Chaturvedi R, Barry D, Coburn L, Asim M, Lewis N . The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis. J Biol Chem. 2010; 286(5):3839-50. PMC: 3030385. DOI: 10.1074/jbc.M110.176719. View

19.

Higgins L, Frankel G, Douce G, Dougan G, MacDonald T . Citrobacter rodentium infection in mice elicits a mucosal Th1 cytokine response and lesions similar to those in murine inflammatory bowel disease. Infect Immun. 1999; 67(6):3031-9. PMC: 96617. DOI: 10.1128/IAI.67.6.3031-3039.1999. View

20.

Chyla B, Moreno-Miralles I, Steapleton M, Ann Thompson M, Bhaskara S, Engel M . Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Mol Cell Biol. 2008; 28(20):6234-47. PMC: 2577421. DOI: 10.1128/MCB.00404-08. View