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

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 in myeloid and lymphoid malignancies. Tet1-deficient cells showed decreased localization of DNMT3A in the heterochromatin compartment compared with WT cells, pointing to a functional interaction between TET and DNMT proteins and providing a potential explanation for the hypomethylation observed in TET-deficient genomes. Our data suggest that TET loss of function may at least partially underlie the characteristic pattern of global hypomethylation coupled to regional hypermethylation observed in diverse cancer genomes, and highlight the potential contribution of heterochromatin hypomethylation to oncogenesis.

TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

“…Given this paradigm, one might expect ESCs to show a global methylation increase upon TET loss, as this would shift the balance in the favor of DNMT3 activity. Counterintuitively, and as previously noted in cancer cells 41 , a slight decrease was also observed in cells lacking TETs compared with matched WT (Extended Data Fig. 10d).…”

Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals

“…In contrast to our findings in TET catalytic mutant ESCs, TET knockout ESCs do not appear to exhibit global hypermethylation 58 . This discrepancy might be explained by recent findings demonstrating that TET proteins influence global DNA methylation not only via their catalytic activity but also by their genomic binding 119,120 . Knockout of TET proteins results in a seemingly paradoxical loss of DNA methylation at repetitive elements like LINEs and LTRs due to a global redistribution of DNMT3A from heterochromatin to euchromatic sites previously occupied by TETs.…”

Tet3 regulates cellular identity and DNA methylation in neural progenitor cells

“…Furthermore, in mouse ES cells, it has been shown that Tet2 knockdown results in both loss of 5hmC and 5mC at DMRs and promoters, while only few DMRs show the expected loss of 5hmC and gain of 5mC [51]. More recently, another study from the Rao lab reported that TET deficiency in diverse cell types resulted in localized increases in DNA methylation in active euchromatic regions, concurrently with unexpected losses of DNA methylation and reactivation of repeat elements [52].…”