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PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

ABSTRACT: The arginine methyltransferase PRMT6 (protein arginine methyltransferase 6) has been shown recently to regulate DNA repair and gene expression. As arginine methylation of histones is an important mechanism in transcriptional regulation, we asked whether PRMT6 possesses activity toward histones. We show here that PRMT6 methylates histone H3 at R2 and histones H4/H2A at R3 in vitro. Overexpression and knockdown analysis identify PRMT6 as the major H3 R2 methyltransferase in vivo. We find that H3 R2 methylation inhibits H3 K4 trimethylation and recruitment of WDR5, a subunit of the MLL (mixed lineage leukemia) K4 methyltransferase complex, to histone H3 in vitro. Upon PRMT6 overexpression, transcription of Hox genes and Myc-dependent genes, both well-known targets of H3 K4 trimethylation, decreases. This transcriptional repression coincides with enhanced occurrence of H3 R2 methylation and PRMT6 as well as reduced levels of H3 K4 trimethylation and MLL1/WDR5 recruitment at the HoxA2 gene. Upon retinoic acid-induced transcriptional activation of HoxA2 in a cell model of neuronal differentiation, PRMT6 recruitment and H3 R2 methylation are diminished and H3 K4 trimethylation increases at the gene. Our findings identify PRMT6 as the mammalian methyltransferase for H3 R2 and establish the enzyme as a crucial negative regulator of H3 K4 trimethylation and transcriptional activation.

SUBMITTER: Hyllus D

PROVIDER: S-EPMC2113036 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

Hyllus Dawin D Stein Claudia C Schnabel Kristin K Schiltz Emile E Imhof Axel A Dou Yali Y Hsieh James J Bauer Uta-Maria UM

Genes & development 20071201 24

The arginine methyltransferase PRMT6 (protein arginine methyltransferase 6) has been shown recently to regulate DNA repair and gene expression. As arginine methylation of histones is an important mechanism in transcriptional regulation, we asked whether PRMT6 possesses activity toward histones. We show here that PRMT6 methylates histone H3 at R2 and histones H4/H2A at R3 in vitro. Overexpression and knockdown analysis identify PRMT6 as the major H3 R2 methyltransferase in vivo. We find that H3 R ...[more]

PMID: 18079182

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Project description:Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.

Dataset Information

PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

Publications

PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

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