Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene

Lauren B Auriemma,Shaili Shah,Lara M Linden,Melissa A Henriksen

doi:10.1186/1756-8935-5-2

Lauren B Auriemma, Shaili Shah + Show 2 more

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https://doi.org/10.1186/1756-8935-5-2

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Abstract

BackgroundThe tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-γ signaling.ResultsRNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well.ConclusionsTaken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.

Highlights

The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors
The results suggest that multiple endocrine neoplasia type 1 (MEN1) and H3K4me2 function to maintain the fidelity of the interferon regulatory factor 1 (IRF1) core promoter transcriptional start site and a chromatin environment that efficiently promotes mRNA processing
The H3K4me2 profile at IRF1 is altered by MEN1 depletion Previously, we profiled H3K4me2 and -me3 in response to IFN-g induction of signal transducer and activator of transcription 1 (STAT1) signaling at the IRF1 gene, using chromatin immunoprecipitation (ChIP) [18]

Summary

Introduction

The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-g signaling. The HMT activity of the four other Set1-like complexes derives from the mixed lineage leukemia (MLL) family of proteins (MLL1 to MLL4), but how their gene targets are specified is not known [4]. All the human Set1-like complexes share a quartet of proteins, absent, small, homeobox-like Drosophila (ASH2L), retinoblastoma binding protein 5 (RbP5), WD repeat domain 5 (WDR5) and human dosage compensation-related protein (hDPY-30) [5], but the interacting proteins menin (MEN1) and pax transactivation domain-interacting protein (PTIP) are respectively specific to the MLL1/MLL2 and the MLL3/MLL4 complexes

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