Paradoxical association of TET loss of function with genome-wide DNA hypomethylation.

Proceedings of the National Academy of Sciences of the United States of America
Isaac F López-MoyadoAnjana Rao

Abstract

Cancer genomes are characterized by focal increases in DNA methylation, co-occurring with widespread hypomethylation. Here, we show that TET loss of function results in a similar genomic footprint. Both 5hmC in wild-type (WT) genomes and DNA hypermethylation in TET-deficient genomes are largely confined to the active euchromatic compartment, consistent with the known functions of TET proteins in DNA demethylation and the known distribution of 5hmC at transcribed genes and active enhancers. In contrast, an unexpected DNA hypomethylation noted in multiple TET-deficient genomes is primarily observed in the heterochromatin compartment. In a mouse model of T cell lymphoma driven by TET deficiency (Tet2/3 DKO T cells), genomic analysis of malignant T cells revealed DNA hypomethylation in the heterochromatic genomic compartment, as well as reactivation of repeat elements and enrichment for single-nucleotide alterations, primarily in heterochromatic regions of the genome. Moreover, hematopoietic stem/precursor cells (HSPCs) doubly deficient for Tet2 and Dnmt3a displayed greater losses of DNA methylation than HSPCs singly deficient for Tet2 or Dnmt3a alone, potentially explaining the unexpected synergy between DNMT3A and TET2 mutations ...Continue Reading

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Citations

Oct 28, 2019·Cellular and Molecular Life Sciences : CMLS·Mafalda SantiagoC Joana Marques
May 20, 2020·Current Opinion in Hematology·Thomas Clapes, Eirini Trompouki
Sep 14, 2019·Cells·Anna-Maria BarciszewskaMirosława Naskręt-Barciszewska
Jun 7, 2020·Nature Genetics·Isaac F López-Moyado, Anjana Rao
Nov 26, 2020·Nature Communications·Christopher B MulhollandHeinrich Leonhardt
Feb 2, 2021·Frontiers in Cell and Developmental Biology·Nikolas James TsiouplisAgeliki Tsagaratou
Mar 28, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Xuan MingYingfeng Li
Dec 29, 2020·Seminars in Cancer Biology·Urszula Oleksiewicz, Marta Machnik
May 12, 2021·Genome Biology·Natasha Jansz, Geoffrey J Faulkner
May 22, 2021·Frontiers in Genetics·John P BrabsonLuisa Cimmino
Jun 12, 2021·The Spine Journal : Official Journal of the North American Spine Society·Yuya KawaraiLaura S Stone
Jun 15, 2021·Trends in Genetics : TIG·Atsuya Nishiyama, Makoto Nakanishi
Jul 25, 2021·International Journal of Molecular Sciences·Darya KaplunSvetlana Zhenilo
Jul 22, 2021·EMBO Reports·Xiaojing YueAnjana Rao

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