H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation

Abstract

Epigenetic silencing in mammals involves DNA methylation and posttranslational modifications of core histones. Here we show that the H1 linker histone plays a key role in regulating both DNA methylation and histone H3 methylation at the H19 and Gtl2 loci in mouse ES cells. Some, but not all, murine H1 subtypes interact with DNA methyltransferases DNMT1 and DNMT3B. The interactions are direct and require a portion of the H1 C-terminal domain. Expression of an H1 subtype that interacts with DNMT1 and DNMT3B in ES cells leads to their recruitment and DNA methylation of the H19 and Gtl2 imprinting control regions. H1 also interferes with binding of the SET7/9 histone methyltransferase to the imprinting control regions, inhibiting production of an activating methylation mark on histone H3 lysine 4. H1-dependent recruitment of DNMT1 and DNMT3B and interference with the binding of SET7/9 also were observed with chromatin reconstituted in vitro. The data support a model in which H1 plays an active role in helping direct two processes that lead to the formation of epigenetic silencing marks. The data also provide evidence for functional differences among the H1 subtypes expressed in somatic mammalian cells.mouse embryonic stem cell | H1 histone triple knockout T wo major types of epigenetic marks occur in mammalian genomes, DNA methylation and posttranslational modifications of histones (1, 2). The methylation of cytosines in mammalian DNA occurs primarily at CpG dinucleotides and is essential for normal mammalian development (1, 3). Perturbations of DNA methylation patterns are thought to play a role in cancer development (4). There are two classes of mammalian DNA methyltransferases (DNMTs), one that functions primarily to establish DNA methylation de novo (DNMT3A and DNMT3B) and the other to maintain it (DNMT1) (3). DNA methylation can have profound effects on gene expression and is most often associated with transcriptional silencing (1, 2). Accumulating evidence indicates the existence of crosstalk between the DNA methylation and core histone modification systems (1, 2). For example, mouse ES cells deficient for the histone H3 lysine 9 (H3K9) methyltransferases Suv39h1/h2 exhibit hypomethylation of CpGs at a subset of repetitive DNA elements (5). Additionally, several lines of evidence indicate that the presence of unmethylated lysine 4 of histone H3 (H3K4) in chromatin favors de novo methylation of DNA (6-9). Despite these advances, the factors in chromatin that coordinate DNA methylation and histone H3 methylation have not been identified.In this study, we investigated the role of the linker histone H1 in regulating DNA methylation and histone H3 methylation at the H19 and Gtl2 loci in mouse ES cells. H1 is the most distinct of the five histone proteins (H1, H2A, H2B, H3, and H4) in chromatin (10,11). Mammals contain at least eight histone H1 subtypes or variants that differ in amino acid sequences and expression during development (12-14). Functional differences among these subtypes have been difficult to identif...

Independent Biological and Biochemical Functions for Individual Structural Domains of Drosophila Linker Histone H1

“…The H1(0) CTD was also reported to bind and stimulate the activity of the apoptotic nuclease, DNA fragmentation factor DFF40/caspase-activated DNase (33). Recently, we reported that certain murine H1 subtypes directly interact with DNA methyltransferases DNMT1 and DNMT3B, recruiting them to chromatin to promote DNA methylation and gene silencing (8). A high degree of specificity was observed for these interactions because only certain H1 subtypes interact with these DNA methyltransferases.…”

“…H1 also facilitates the folding of chromatin into more compact structures. In addition to these architectural roles, there are now an increasing number of reports describing interactions between H1 linker histones and a variety of other nuclear proteins (6), including functional interactions between H1, histone-modifying enzymes, and DNA methyltransferases that lead to modulation of epigenetic marking of chromatin (7,8). In this context, it is notable that the binding of linker histones to chromatin is highly dynamic, with residence times much shorter than that of the core histones (9).…”

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

“…As an example, SNP2 (rs12333117), associated with age at onset in the present study, is located in a downstream region, in a DNAse region (T-47D) and it is predicted to alter several motifs that overlap the recognition sequences of transcription factors such as AP-1/Jun, suggesting possible factorfactor interactions. There is also evidence that this SNP could modify the promoter histone mark H1, which plays an active role in the formation of epigenetic silencing marks (Yang et al 2013). Another example refers to the SNP4 (rs645649), included in the identified risk haplotype and that is located in an intronic region where two proteins bound: SUZ12 (involved in methylation processes leading to transcriptional repression of the affected target genes) and ZNF263 (implicated in basic cellular processes as a transcriptional repressor).…”

Chromatin reprogramming during the somatic-to-reproductive cell fate transition in plants

“…However, H1 stoichiometry in the plant nucleus, besides its impact on the structural organization of chromatin, is likely to influence DNA methylation patterns as it does in both plant and animal somatic cells (Fan et al, 2005;Wierzbicki and Jerzmanowski, 2005;Yang et al, 2013;Zemach et al, 2013). H2A.Z depletion in the MMC further increases the potential for reprogramming of DNA methylation because these two marks are mutually exclusive (Zilberman, 2008).…”