Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation.
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.
Barrero
María J
MJ
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Malik
Sohail
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D018938:Caco-2 Cells; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D019175:DNA Methylation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000737:chemistry*; D008969:Molecular Sequence Data; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D008780:Methyltransferases; C099988:PRMT1 protein, human; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases