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Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation.

ABSTRACT: Nuclear receptors, like other transcriptional activators, switch on gene transcription by recruiting a complex network of coregulatory proteins. Here, we have identified the arginine methyltransferase PRMT1 as a coactivator for HNF4, an orphan nuclear receptor that regulates the expression of genes involved in diverse metabolic pathways. Remarkably, PRMT1, whose methylation activity on histone H4 strongly correlates with induction of HNF4 target genes in differentiating enterocytes, regulates HNF4 activity through a bipartite mechanism. First, PRMT1 binds and methylates the HNF4 DNA-binding domain (DBD), thereby enhancing the affinity of HNF4 for its binding site. Second, PRMT1 is recruited to the HNF4 ligand-binding domain (LBD) through a mechanism that involves the p160 family of coactivators and methylates histone H4 at arginine 3. This, together with recruitment of the histone acetyltransferase p300, leads to nucleosomal alterations and subsequent RNA polymerase II preinitiation complex formation.

SUBMITTER: Barrero MJ

PROVIDER: S-EPMC1647399 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation.

Barrero María J MJ Malik Sohail S

Molecular cell 20061001 2

Nuclear receptors, like other transcriptional activators, switch on gene transcription by recruiting a complex network of coregulatory proteins. Here, we have identified the arginine methyltransferase PRMT1 as a coactivator for HNF4, an orphan nuclear receptor that regulates the expression of genes involved in diverse metabolic pathways. Remarkably, PRMT1, whose methylation activity on histone H4 strongly correlates with induction of HNF4 target genes in differentiating enterocytes, regulates HN ...[more]

PMID: 17052457

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Project description:BackgroundNuclear receptors are a large structural class of transcription factors that act with their co-regulators and repressors to maintain a variety of biological and physiological processes such as metabolism, development and reproduction. They are activated through the binding of small ligands, which can be replaced by drug molecules, making nuclear receptors promising drug targets. Transcriptional regulation of the genes that encode them is central to gaining a deeper understanding of the diversity of their biochemical and biophysical roles and their role in disease and therapy. Even though they share evolutionary history, nuclear receptor genes have fundamentally different expression patterns, ranging from ubiquitously expressed to tissue-specific and spatiotemporally complex. However, current understanding of regulation in nuclear receptor gene family is still nascent.Methodology/principal findingsIn this study, we investigate the relationship between long-range regulation of nuclear receptor family and their known functionality. Towards this goal, we identify the nuclear receptor genes that are potential targets based on counts of highly conserved non-coding elements. We validate our results using publicly available expression (RNA-seq) and histone modification (ChIP-seq) data from the ENCODE project. We find that nuclear receptor genes involved in developmental roles show strong evidence of long-range mechanism of transcription regulation with distinct cis-regulatory content they feature clusters of highly conserved non-coding elements distributed in regions spanning several Megabases, long and multiple CpG islands, bivalent promoter marks and statistically significant higher enrichment of enhancer mark around their gene loci. On the other hand nuclear receptor genes that are involved in tissue-specific roles lack these features, having simple transcriptional controls and a greater variety of mechanisms for producing paralogs. We further examine the combinatorial patterns of histone maps associated with dynamic functional elements in order to explore the regulatory landscape of the gene family. The results show that our proposed classification capturing long-range regulation is strongly indicative of the functional roles of the nuclear receptors compared to existing classifications.Conclusions/significanceWe present a new classification for nuclear receptor gene family capturing whether a nuclear receptor is a possible target of long-range regulation or not. We compare our classification to existing structural (mechanism of action) and homology-based classifications. Our results show that understanding long-range regulation of nuclear receptors can provide key insight into their functional roles as well as evolutionary history; and this strongly merits further study.

Dataset Information

Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation.

Publications

Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation.

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