The histone demethylase PHF8 is a molecular safeguard of the IFNγ response

Abstract

A precise immune response is essential for cellular homeostasis and animal survival. The paramount importance of its control is reflected by the fact that its non-specific activation leads to inflammatory events that ultimately contribute to the appearance of many chronic diseases. However, the molecular mechanisms preventing non-specific activation and allowing a quick response upon signal activation are not yet fully understood. In this paper we uncover a new function of PHF8 blocking signal independent activation of immune gene promoters. Affinity purifications coupled with mass spectrometry analysis identified SIN3A and HDAC1 corepressors as new PHF8 interacting partners. Further molecular analysis demonstrated that prior to interferon gamma (IFNγ) stimulation, PHF8 is bound to a subset of IFNγ-responsive promoters. Through the association with HDAC1 and SIN3A, PHF8 keeps the promoters in a silent state, maintaining low levels of H4K20me1. Upon IFNγ treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, correlating with an increase in H4K20me1 and transcriptional activation. Our data strongly indicate that in addition to its well-characterized function as a coactivator, PHF8 safeguards transcription to allow an accurate immune response.

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

“…These data are in accordance with the activator role proposed for PHF2 (17). Nevertheless, the fact that 34% of the direct targets became up-regulated upon PHF2 depletion, suggest a potential role of PHF2 contributing to transcriptional repression or preventing activation as it has been demonstrated for another member of the KDM7 family, PHF8, in a different cellular context (30). Enrichment analysis of GO terms over the 601 PHF2 direct target genes showed that the most enriched were associated with cell cycle categories, particularly G1/S transition (E2f2/3/7/8, Cdc7, Cdc25a, Cdk4, and Mcm3/4/8), DNA replication (Orc1/2/6 and Pcna), mitosis (Cdk1, Smc2/3/4, Aurkb, and Topo2a), as well as chromatin activity (Cenpa, Kdm1b, Hat1, Parp1, and Prmt5) ( Fig.…”

“…Lentiviral Transduction. Lentiviral transduction was carried out as previously described (30,61). Extended protocol is provided in SI Appendix, Materials and Methods.…”

Lineage specific transcription factors and epigenetic regulators mediate TGFβ-dependent enhancer activation

“…Lentiviral transduction was carried out as previously described ( 36 ). Extended protocol is provided in Supplementary Materials and Methods .…”

Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses

“…In HeLa S3 cells, PHF8 bound to a subset of IFN‐responsive promoters and, through association with co‐repressors such as HDAC1 and SIN3A, PHF8 kept these promoters inactive, maintaining H4K20me1 at low levels. INF‐γ stimulation promoted PHF8 phosphorylation from Extracellular signal‐regulated kinase 2 (ERK2), resulting in its removal from the promoters and active gene transcription (Asensio‐Juan et al, ). Chromatin modifications affected by histone demethylases in the context of macrophage activation is presented in Table .…”