Figure 7

Models for the multi-dimensional functions of TETs in mediating DNA methylation and hydroxymethylation. (A) TET family members enrich 5hmC at CGI shores to provide a protective boundary against aberrant hypermethylation (i). In the absence of TETs, 5hmC cannot be established, permitting the aberrant expansion of 5mC into the CGI (ii). (B) In the normal pluripotent state, TETs eliminate 5hmC from promoters and remove both 5mC and 5hmC from gene bodies of a subset of highly transcriptionally active H3K4me3- and H3K36me3-marked genes (i). TETs mediate hydroxymethylation and promote a low level of methylation at H3K27me3-marked promoters (ii). At H2AK119ub-marked promoters TET proteins enrich 5hmC and promote turnover of cytosine modifications by mediating demethylation of 5mC (iii). In the event of TET mutation or other TET functional disruption (like decreased expression), these distinct epigenetic patterns are lost, making loci vulnerable to changes in transcriptional activity, perhaps by leaving unmodified cytosines available for aberrant DNA methylation by DNMTs or by permitting the binding of chromatin remodelers or repressors such as PRC1 or PRC2.