Immune complexity: molecular methylation controls (Introduction)

by David Turell , Friday, January 22, 2021, 21:17 (1188 days ago) @ David Turell

Very precise molecular interactions to allow or reduce methylation:

https://advances.sciencemag.org/content/7/4/eabb9149?utm_campaign=toc_advances_2021-01-...

"Abstract
5-Methylcytosine (5mC) oxidases, the ten-eleven translocation (TET) proteins, initiate DNA demethylation, but it is unclear how 5mC oxidation is regulated. We show that the protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) is found in complexes with TET proteins and negatively regulates TET activities. Removal of SMCHD1 from mouse embryonic stem (ES) cells induces DNA hypomethylation, preferentially at SMCHD1 target sites and accumulation of 5-hydroxymethylcytosine (5hmC), along with promoter demethylation and activation of the Dux double-homeobox gene. In the absence of SMCHD1, ES cells acquire a two-cell (2c) embryo–like state characterized by activation of an early embryonic transcriptome that is substantially imposed by Dux. Using Smchd1/Tet1/Tet2/Tet3 quadruple-knockout cells, we show that DNA demethylation, activation of Dux, and other genes upon SMCHD1 loss depend on TET proteins. These data identify SMCHD1 as an antagonist of the 2c-like state of ES cells and of TET-mediated DNA demethylation.

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"Our data suggest that SMCHD1 is critical for Dux suppression in mESCs, thus controlling the 2c-like state. Furthermore, SMCHD1 plays a key role in de novo methylation of CpG islands on the inactive X chromosome during mouse development (23). Recent data have shown, however, that loss of SMCHD1 in somatic cells does not lead to X chromosome reactivation (24, 25). Together, the existing data suggest that SMCHD1 functions in promoting de novo DNA methylation during development rather than in mediating methylation maintenance, and we propose the following mechanism: SMCHD1 operates in these critical DNA methylation events by inhibiting TET-mediated 5mC oxidation and demethylation at its target regions, as we show in this study, thereby shifting the balance of methylation versus demethylation toward the methylated state (Fig. 7H). When SMCHD1 is lost, but DNA methylation remains high in the absence of TETs (reduced DNA methylation dynamics), Dux expression may not be occurring because of inhibition of transcription by DNA methylation. On the other hand, in absence of SMCHD1 and presence of TET activity, and thus higher methylation-demethylation dynamics, Dux will be activated. This pathway is important in inhibiting the totipotent (2c-like state) of ES cells. Although a role of SMCHD1 in inactivation of Dux in late 2c mouse embryos has recently been proposed (58), this event seems initially independent of DNA methylation inasmuch as the Dux promoter region is almost completely unmethylated in 2c and 4c mouse embryos (59); therefore, the de novo methylation events must occur later during development. Further studies are needed to confirm whether SMCHD1 is responsible for the remethylation of the Dux locus during early embryo development and whether inhibition of TET proteins plays an important role in this process."

Comment: The highly complex interactions are very difficult to study as the methods sections I've skipped over show. Only design can produce this type of control mechanism.