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Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE146250 | GEO | 2021/12/14

REPOSITORIES: GEO

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Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation.

Project description:Regulatory T (Treg) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how Treg cells are mechanistically induced in vitro (iTreg) and stabilized via transcriptional regulation of Treg lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis-regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iTreg induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iTreg cell lineage specification.

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Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation [WGBS]

Project description:Regulatory T (Treg) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how mechanistically Treg cells are induced and stabilized via transcriptional regulation of Treg lineage–specifying factor Foxp3. Acetylation of histone tails in the Foxp3 locus is induced during Treg cell development and required in cis for the initiation of Foxp3 transcription. Upon induction, histone acetylation signal largely acts in trans to sustain Foxp3 transcription via multiple factors. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis-regulatory elements particularly enhancer CNS2 increases chromatin accessibility and protein binding, drastically stabilizing Foxp3 transcription, although histone acetylation still regulates global gene expression. These processes transform stochastic Treg cell induction into a stable cell fate, with the former sensitive and latter resistant to genetic and environmental perturbations. Thus, our study reveals distinct roles of histone acetylation in Foxp3 induction and maintenance, reflecting sequential mechanical switches governing Treg cell lineage specification.

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