Epigenetic Instability of Cytokine and Transcription Factor Gene Loci Underlies Plasticity of the T Helper 17 Cell Lineage

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2010 May 18

PMID 20471290

Citations 155

Authors

Ryuta Mukasa

Anand Balasubramani

Yun Kyung Lee

Sarah K Whitley

Benjamin T Weaver

Yoichiro Shibata

Gregory E Crawford

Robin D Hatton

Casey T Weaver

Affiliations

Soon will be listed here.

Abstract

Phenotypic plasticity of T helper 17 (Th17) cells suggests instability of chromatin structure of key genes of this lineage. We identified epigenetic modifications across the clustered Il17a and Il17f and the Ifng loci before and after differential IL-12 or TGF-beta cytokine signaling, which induce divergent fates of Th17 cell precursors. We found that Th17 cell precursors had substantial remodeling of the Ifng locus, but underwent critical additional modifications to enable high expression when stimulated by IL-12. Permissive modifications across the Il17a-Il17f locus were amplified by TGF-beta signaling in Th17 cells, but were rapidly reversed downstream of IL-12-induced silencing of the Rorc gene by the transcription factors STAT4 and T-bet. These findings reveal substantial chromatin instability of key transcription factor and cytokine genes of Th17 cells and support a model of Th17 cell lineage plasticity in which cell-extrinsic factors modulate Th17 cell fates through differential effects on the epigenetic status of Th17 cell lineage factors.

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