RT Journal Article SR Electronic T1 Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism JF bioRxiv FD Cold Spring Harbor Laboratory SP 820845 DO 10.1101/820845 A1 Adam P Cribbs A1 Stefan Terlecki-Zaniewicz A1 Martin Philpott A1 Jeroen Baardman A1 David Ahern A1 Morten Lindow A1 Susanna Obad A1 Henrik Oerum A1 Brante Sampey A1 Palwinder Mander A1 Henry Penn A1 Paul Wordsworth A1 Paul Bowness A1 Rab K Prinjha A1 Menno de Winther A1 Marc Feldmann A1 Udo Oppermann YR 2019 UL http://biorxiv.org/content/early/2019/10/30/820845.abstract AB T helper (Th) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORĪ³t during Th17 differentiation, whereas in mature Th17 cells an altered transcriptional program leads to a profound metabolic reprogramming with concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single cell analysis reveals a specific shift from highly inflammatory cell subsets towards a resting state upon demethylase inhibition. The root cause of the observed anti-inflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1 and c-myc. Overall, this leads to reduced mitochondrial biogenesis resulting in a metabolic switch with concomitant anti-inflammatory effects. These data are consistent with an opposing effect of GSK-J4 on Th17 T-cell differentiation pathways directly related to proliferation and effector cytokine profiles.