TET1 and TDG suppress intestinal tumorigenesis by down-regulating the inflammatory and immune response pathways
Year: 2019
Type: preprint
Abstract: Introduction Aberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and DNA repair enzyme Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing, respectively, novel oxidized cytosine species. Mutations of TET1 and TDG , and alterations of the levels of oxidized cytosine species have been identified in human CRC cases, but the biological significance of the TET-TDG demethylation axis in intestinal tumorigenesis is unclear. Material and Methods We generated Apc Min mice with additional inactivation of Tet1 and/or Tdg , and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively. Results Tet1- and/or Tdg -deficient Apc Min mice show enhanced intestinal tumorigenesis in comparison to wild type Tet1 and Tdg Apc Min mice. Specifically, Tet1 and/or Tdg -deficient Apc Min adenomas manifested increased size or features of erosion and stroma activation. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg -deficient Apc Min mice, and hypermethylation of CpG islands in Tet1 -deficient Apc Min mice. In addition, RNA sequencing showed upregulation of genes in inflammatory and immune response pathways in Tet1 -and Tdg -mutant colonic adenomas compared to control Apc Min adenomas. Conclusions Taken together, these findings demonstrate the important role of active DNA demethylation mediated by TET-TDG in reducing intestinal tumor formation, by modulating the epigenome and inflammatory/immune responses. This study highlights a novel mechanism of epigenetic deregulation during intestinal tumorigenesis with diagnostic, therapeutic and prognostic implications.
DOI: 10.1101/676445
Authors: Rossella Tricarico, Jozef Madzo, Gabrielle Scher, Shinji Maegawa, Jaroslav Jelinek, Carly Scher, Wen-Chi Chang, Emmanuelle Nicolas, Yan Zhou, Michael Slifker, Karthik Devarajan, Kathy Q. Cai, Pamela Nakajima, Jinfei Xu, Pietro Mancuso, Valentina Doneddu, Luigi Bagella, Justin Ingram, Siddharth Balachandran, Iuliia Peshkova, Ekaterina Koltsova, Sergei Grivennikov, Timothy J. Yen, Jean-Pierre Issa, Alfonso Bellacosa
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
Awards: G9000027172, G9000114830
OpenAlex ID: W2952266966