Recruitment of Histone Methyltransferase Ehmt1 to Foxp3 TSDR Counteracts Differentiation of Induced Regulatory T Cells
| Autor: | Katharina Hecklau, Christian H. Gabriel, Andreas Radbruch, Christian Sommer, Matthias Selbach, Martin Karl, Anna Floriane Hennig, Ria Baumgrass, Melanie Venzke |
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| Rok vydání: | 2019 |
| Předmět: |
Kruppel-Like Transcription Factors
Nerve Tissue Proteins chemical and pharmacologic phenomena Ascorbic Acid T-Lymphocytes Regulatory Epigenesis Genetic Histones 03 medical and health sciences EHMT1 0302 clinical medicine Structural Biology medicine Animals Epigenetics Molecular Biology Gene Transcription factor 030304 developmental biology Mice Inbred BALB C 0303 health sciences Base Sequence Models Genetic biology FOXP3 Cell Differentiation Forkhead Transcription Factors hemic and immune systems Histone-Lysine N-Methyltransferase T helper cell DNA Methylation Demethylation Cell biology Mice Inbred C57BL medicine.anatomical_structure Histone Histone methyltransferase biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Journal of Molecular Biology. 431:3606-3625 |
| ISSN: | 0022-2836 |
| Popis: | Differentiation toward 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 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. |
| Databáze: | OpenAIRE |
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