title: Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus.
abstract: Stable expression of Foxp3 in regulatory T cells (Tregs) depends on DNA demethylation at the Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the Foxp3 locus. The TSDR is selectively demethylated in ex vivo Tregs purified from secondary lymphoid organs, but it is unclear at which stage of Treg development demethylation takes place. In this study, we show that commitment to a stable lineage occurred during early stages of murine thymic Treg development by engraving of lineage-specific epigenetic marks in parallel with establishment of a Treg-specific gene expression profile. TSDR demethylation was achieved through an active mechanism and involved enzymes of the ten-eleven-translocation family and hydroxylation of methylated cytosines, a modification that is implicated as an initiating step of mitosis-independent DNA demethylation pathways and has not yet been observed at specific loci during immune cell differentiation. Together, our results demonstrate that initiating TSDR demethylation during early stages of thymic Treg development commences stabilization of Foxp3 expression and guarantees full functionality and long-term lineage stability of Tregs.
authors: Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
authors: Aras
authors: A
authors: Toker
authors: Dirk
authors: D
authors: Engelbert
authors: Garima
authors: G
authors: Garg
authors: Julia K
authors: JK
authors: Polansky
authors: Stefan
authors: S
authors: Floess
authors: Takahisa
authors: T
authors: Miyao
authors: Udo
authors: U
authors: Baron
authors: Sandra
authors: S
authors: Düber
authors: Robert
authors: R
authors: Geffers
authors: Pascal
authors: P
authors: Giehr
authors: Sonja
authors: S
authors: Schallenberg
authors: Karsten
authors: K
authors: Kretschmer
authors: Sven
authors: S
authors: Olek
authors: Jörn
authors: J
authors: Walter
authors: Siegfried
authors: S
authors: Weiss
authors: Shohei
authors: S
authors: Hori
authors: Alf
authors: A
authors: Hamann
authors: Jochen
authors: J
authors: Huehn
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D018899:CpG Islands; D003596:Cytosine / Q000737:chemistry; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D023061:Gene Order; D008297:Male; D051379:Mice; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D003596:Cytosine