TET1 and TDG suppress intestinal tumorigenesis by down regulating the inflammatory and immune response pathways

Tricarico, R.; Madzo, J.; Scher, G.; Maegawa, S.; Jelinek, J.; Scher, C.; Chang, W.-C.; Nicolas, E.; Zhou, Y.; Slifker, M.; Devarajan, K.; Cai, K. Q.; Nakajima, P.; Xu, J.; Mancuso, P.; Doneddu, V.; Bagella, L. M.; Ingram, J.; Balachandran, S.; Peshkova, I.; Koltsova, E.; Grivennikov, S.; Yen, T. J.; Issa, J.-P.; Bellacosa, A.

doi:10.1101/676445

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bioRxiv · 10.1101/676445

TET1 and TDG suppress intestinal tumorigenesis by down regulating the inflammatory and immune response pathways

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Abstract

IntroductionAberrant 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.\n\nMaterial and MethodsWe generated ApcMin mice with additional inactivation of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively.\n\nResultsTet1- and/or Tdg-deficient ApcMin mice show enhanced intestinal tumorigenesis in comparison to wild type Tet1 and Tdg ApcMin mice. Specifically, Tet1 and/or Tdg-deficient ApcMin 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 ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin 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 ApcMin adenomas.\n\nConclusionsTaken 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.

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Tricarico, R., Madzo, J., Scher, G., Maegawa, S., Jelinek, J., Scher, C., Chang, W.-C., Nicolas, E., Zhou, Y., Slifker, M., Devarajan, K., Cai, K. Q., Nakajima, P., Xu, J., Mancuso, P., Doneddu, V., Bagella, L. M., Ingram, J., Balachandran, S., Peshkova, I., Koltsova, E., Grivennikov, S., Yen, T. J., Issa, J.-P., Bellacosa, A.. 2019-06-21. TET1 and TDG suppress intestinal tumorigenesis by down regulating the inflammatory and immune response pathways. https://doi.org/10.1101/676445

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