Components of the DNA Methylation System of Chromatin Control Are RNA-binding Proteins

Abstract

The view that autosomal gene expression is controlled exclusively by protein trans-acting factors has been challenged recently by the identification of RNA molecules that regulate chromatin. In the majority of cases where RNA molecules are implicated in DNA control, the molecular mechanisms are unknown, in large part because the RNA⅐protein complexes are uncharacterized. Here, we identify a novel set of RNAbinding proteins that are well known for their function in chromatin regulation. The RNA-interacting proteins are components of the mammalian DNA methylation system. Genomic methylation controls chromatin in the context of transposon silencing, imprinting, and X chromosome dosage compensation. DNA methyltransferases (DNMTs) catalyze methylation of cytosines in CGs. The methyl-CGs are recognized by methyl-DNA-binding domain (MBD) proteins, which recruit histone deacetylases and chromatin remodeling proteins to effect silencing. We show that a subset of the DNMTs and MBD proteins can form RNA⅐protein complexes. We characterize the MBD protein RNA-binding activity and show that it is distinct from the methyl-CG-binding domain and mediates a high affinity interaction with RNA. The RNA and methyl-CG binding properties of the MBD proteins are mutually exclusive. We speculate that DNMTs and MBD proteins allow RNA molecules to participate in DNA methylation-mediated chromatin control.

New meaning in the message: Noncoding RNAs and their role in retinal development

“…Cis and transacting mechanisms of action for OSTs, moreover, need not be mutually exclusive. Interestingly, a number of chromatin-modifying proteins, including both components of the PRC2 DNA methyltransferase complexes, directly bind to RNA (Zhang et al, 2004;Bernstein et al, 2006;Jeffery and Nakielny, 2004). Perhaps ncRNAs direct histone modifications in chromatin to influence expression of transcription factors.…”

RNA regulation of epigenetic processes

“…These include DNA methyltransferases and methyl DNA binding domain proteins, (16) heterochromatin protein 1 (HP1), (17) the multi-KH domain protein DPP1 which suppresses heterochromatin-mediated silencing in Drosophila, (18) and domains commonly found in chromatin remodelling enzymes and effector proteins such as SET domains, tudor domains and chromodomains. (8,(19)(20)(21) Moreover, the vast majority of the genomes of all metazoans, from worms to human, and probably plants, is transcribed in a developmentally regulated manner, mainly into ncRNAs with complex patterns of overlapping and interlacing transcripts from both strands, (9,10) potentially providing a rich source of regulatory molecules to guide the epigenetic trajectories of development.…”

NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of the Kcnq1 Imprinting Control Region

“…Loss of methylation spreading in the flanking H19 coding region of PS4CAT1-3 further reinforces the suggestion that the antisense transcription is involved in the modification of chromatin. Con- sistent with this presumption, in a recent study (22), it has been documented that the RNA component also plays a crucial part in recruiting DNA methyltransferases and methyl-specific CpG binding proteins complexed with histone deacetylases.…”