title: Epigenetic Thpok silencing limits the time window to choose CD4(+) helper-lineage fate in the thymus.
abstract: CD4(+) helper and CD8(+) cytotoxic T cells differentiate from common precursors in the thymus after T-cell receptor (TCR)-mediated selection. Commitment to the helper lineage depends on persistent TCR signals and expression of the ThPOK transcription factor, whereas a ThPOK cis-regulatory element, ThPOK silencer, represses Thpok gene expression during commitment to the cytotoxic lineage. Here, we show that silencer-mediated alterations of chromatin structures in cytotoxic-lineage thymocytes establish a repressive state that is epigenetically inherited in peripheral CD8(+) T cells even after removal of the silencer. When silencer activity is enhanced in helper-lineage cells, by increasing its copy number, a similar heritable Thpok silencing occurs. Epigenetic locking of the Thpok locus may therefore be an independent event from commitment to the cytotoxic lineage. These findings imply that long-lasting TCR signals are needed to establish stable Thpok expression activity to commit to helper T-cell fate and that full commitment to the helper lineage requires persistent reversal of silencer activity during a particular time window.
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.forename: Sawako
authors.initials: S
authors.lastname: Muroi
authors.forename: Wooseok
authors.initials: W
authors.lastname: Seo
authors.forename: Risa
authors.initials: R
authors.lastname: Chihara
authors.forename: Chizuko
authors.initials: C
authors.lastname: Miyamoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D051379:Mice; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000276:immunology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C484225:ZBTB7B protein, human