Recruitment of histone methyltransferase Ehmt1 to Foxp3 TSDR counteracts differentiation of induced regulatory T cells

Item Type:	Article
Title:	Recruitment of histone methyltransferase Ehmt1 to Foxp3 TSDR counteracts differentiation of induced regulatory T cells
Creators Name:	Karl, M. and Sommer, C. and Gabriel, C.H. and Hecklau, K. and Venzke, M. and Hennig, A.F. and Radbruch, A. and Selbach, M. and Baumgrass, R.
Abstract:	Differentiation towards CD4 + regulatory T (Treg) cells is essentially dependent on an epigenetic program at Treg signature genes, which involves remodeling of the Treg-specific demethylated regions (TSDRs). In particular, the epigenetic status of the conserved non-coding sequence 2 of Foxp3 (Foxp3 TSDR) determines expression stability of the master transcription factor and thus, Treg lineage identity. However, the molecular mechanisms controlling the epigenetic remodeling at TSDRs in Treg and conventional T (Tcon) cells are largely unknown. Using a combined approach of DNA pull-down and mass spectrometric analysis, we report a novel regulatory mechanism in which transcription factor Wiz recruits the histone methyltransferase Ehmt1 to Foxp3 TSDR. We show that both Wiz and Ehmt1 are crucial for shaping the region with the repressive histone modification H3K9me2 in conventional T cells. Consistently, knocking out either Ehmt1 or Wiz by CRISPR/Cas resulted in the loss of H3K9me2 and enhanced Foxp3 expression during iTreg differentiation. Moreover, the essential role of the Wiz–Ehmt1 interaction as observed at several TSDRs indicates a global function of Ehmt1 in the Treg differentiation program. Using a combined approach of DNA pull-down and mass spectrometric analysis, we report a novel regulatory mechanism in which transcription factor Wiz recruits the histone methyltransferase Ehmt1 to Foxp3 TSDR. We show that both, Wiz and Ehmt1 are crucial for shaping the region with the repressive histone modification H3K9me2 in Tcon cells. Consistently, knocking out either Ehmt1 or Wiz by CRISPR/Cas resulted in the loss of H3K9me2 and enhanced Foxp3 expression during iTreg differentiation. Moreover, the essential role of the Wiz-Ehmt1 interaction as observed at several TSDRs indicates a global function of Ehmt1 in the Treg differentiation program.
Keywords:	Epigenetics, Vitamin C, T Helper Cell, DNA-Pull Down, Mass Spectrometry, Ascorbate, Animals, Mice
Source:	Journal of Molecular Biology
ISSN:	0022-2836
Publisher:	Elsevier
Volume:	431
Number:	19
Page Range:	3606-3625
Date:	6 September 2019
Official Publication:	https://doi.org/10.1016/j.jmb.2019.07.031
PubMed:	View item in PubMed

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