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TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors.
Gonzalez, Edward A; Liu, Yue; Wang, Dahui; Jeziorek, Maciej; Bandyopadhyay, Sheila; Rao, Anjana; Gao, Nan; Etchegaray, Jean-Pierre.
Afiliación
  • Gonzalez EA; Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102.
  • Liu Y; Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102.
  • Wang D; Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102.
  • Jeziorek M; Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102.
  • Bandyopadhyay S; Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102.
  • Rao A; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.
  • Gao N; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
  • Etchegaray JP; Department of Pharmacology and Moores Cancer Center, University of California, La Jolla, CA 92093.
Proc Natl Acad Sci U S A ; 120(37): e2221405120, 2023 09 12.
Article en En | MEDLINE | ID: mdl-37669386
ABSTRACT
DNA methylation functions as a repressive epigenetic mark that can be reversed by the Ten-eleven translocation (TET) family of DNA dioxygenases that sequentially oxidize 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised by DNA base-excision repair factors leading to unmodified cytosines. TET enzymes were recently implicated as potential risk factors for inflammatory bowel disease (IBD), but the contribution of TET-mediated DNA oxidation to intestinal homeostasis and response to environmental stressors are unknown. Here, we show prominent roles of TET3 in regulating mouse intestinal epithelial differentiation and response to luminal stressors. Compared with wild-type littermates, mice with intestinal epithelial cell-specific ablation of Tet3 (Tet3ΔIEC) demonstrated a decreased transcriptome involved in innate immune response, Paneth cell differentiation, and epithelial regeneration. Tet3IEC mice exhibited an elevated susceptibility to enteric pathogen infection that is correlated with a decreased epithelial 5hmC abundance. Infection of human enterocytes or mice with the pathogenic bacteria acutely increased 5hmC abundance. Genome-wide 5hmC profiling revealed a shift of genomic enrichment of 5hmC toward genes involved in activating Notch, Wnt, and autophagy pathways. Furthermore, chemical stressor dextran sulfate sodium (DSS) represses epithelial 5hmC abundance in a temporal fashion, and Tet3IEC mice exhibited increased susceptibility to DSS experimental colitis with reduced regenerative capacity. TET3 is a critical regulator of gut epithelial DNA methylome and transcriptome, especially in response to luminal stressors, for the maintenance of tissue homeostasis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Colitis / Dioxigenasas Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Colitis / Dioxigenasas Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article