Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1)

Lauren J Buro,Edmond Chipumuro,Melissa A Henriksen

doi:10.1186/1756-8935-3-16

Lauren J Buro, Edmond Chipumuro + Show 1 more

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https://doi.org/10.1186/1756-8935-3-16

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Journal: Epigenetics & chromatin	Publication Date: Sep 8, 2010
Citations: 80	License type: cc-by

Affiliation: University of Virginia

Abstract

BackgroundSignal transducer and activator of transcription (STAT) activation of gene expression is both rapid and transient, and when properly executed it affects growth, differentiation, homeostasis and the immune response, but when dysregulated it contributes to human disease. Transcriptional activation is regulated by alterations to the chromatin template. However, the role of histone modification at gene loci that are activated for transcription in response to STAT signaling is poorly defined.ResultsUsing chromatin immunoprecipitation, we profiled several histone modifications during STAT1 activation of the interferon regulatory factor 1 gene (IRF1). Methylated lysine histone proteins H3K4me2, H3K4me3, H3K79me3, H3K36me3 and monoubiquitinated histone ubH2B are dynamic and correlate with interferon (IFN)γ induction of STAT1 activity. Chemical inhibition of H3K4 methylation downregulates IRF1 transcription and decreases RNA polymerase II (Pol II) occupancy at the IRF1 promoter. MEN1, a component of a complex proteins associated with Set1 (COMPASS)-like complex and the hBRE1 component, RNF20, are localized to IRF1 in the uninduced state and are further recruited when IRF1 is activated. RNAi-mediated depletion of RNF20 lowers both ubH2B and H3K4me3, but surprisingly, upregulates IFNγ induced IRF1 transcription. The dynamics of phosphorylation in the C-terminal domain (CTD) of Pol II are disrupted during gene activation as well.ConclusionsH2B monoubiquitination promotes H3K4 methylation, but the E3 ubiquitin ligase, RNF20, is repressive of inducible transcription at the IRF1 gene locus, suggesting that ubH2B can, directly or indirectly, affect Pol II CTD phosphorylation cycling to exert control on ongoing transcription.

Highlights

Signal transducer and activator of transcription (STAT) activation of gene expression is both rapid and transient, and when properly executed it affects growth, differentiation, homeostasis and the immune response, but when dysregulated it contributes to human disease
Histone modifications correlate with inducible signal transducer and activator of transcription 1 (STAT1) activity To investigate chromatin’s contribution to STATinduced gene expression, we generated a detailed profile of the distribution of several histone modifications across the interferon regulatory factor 1 gene (IRF1) gene locus in 2fTGH cells treated with IFNg using chromatin immunoprecipitation (ChIP)
To assay for dynamic changes in histone modification, we collected ChIP data before, during and after STAT activation, having determined that IRF1 gene expression peaked at approximately 90 min and dissipated within 5 h when cells were treated with IFNg for 30 min and returned to normal growth media (Figure 1 and Additional file 1e)

Summary

Introduction

Signal transducer and activator of transcription (STAT) activation of gene expression is both rapid and transient, and when properly executed it affects growth, differentiation, homeostasis and the immune response, but when dysregulated it contributes to human disease. In response to a variety of extracellular ligands, signal transducers and activators of transcription (STATs) are rapidly recruited from their latent state in the cytoplasm to cell surface receptors, where they are phosphorylated by tyrosine kinases. They translocate to the nucleus, bind DNA response elements and drive the transcription of target genes, affecting growth, differentiation, homeostasis and the immune response [1]. Not surprisingly, given their widespread involvement in normal cellular processes, dysregulation of STAT activity contributes to human disease, to cancers. Other negative regulators include the suppressor of cytokine signaling (SOCS) family of proteins, which are induced by cytokine signaling and STAT activation and participate in a negative feedback loop, and the protein inhibitor of activated STAT (PIAS) family of proteins, which can directly inhibit STATs by preventing their DNA binding [4]

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