DNA methylation and the formation of heterochromatin in Neurospora crassa

DNA methylation, heterochromatin protein 1 (HP1), histone H3 lysine 9 (H3K9) methylation, histone deacetylation, and highly repeated sequences are prototypical heterochromatic features, but their interrelationships are not fully understood. Prior work showed that H3K9 methylation directs DNA methylation and histone deacetylation via HP1 in Neurospora crassa and that the histone deacetylase complex HCHC is required for proper DNA methylation. The complex consists of the chromodomain proteins HP1 and chromodomain protein 2 (CDP-2), the histone deacetylase HDA-1, and the AT-hook motif protein CDP-2/HDA-1–associated protein (CHAP). We show that the complex is required for proper chromosome segregation, dissect its function, and characterize interactions among its components. Our analyses revealed the existence of an HP1-based DNA methylation pathway independent of its chromodomain. The pathway partially depends on CHAP but not on the CDP-2 chromodomain. CDP-2 serves as a bridge between the recognition of H3K9 trimethylation (H3K9me3) by HP1 and the histone deacetylase activity of HDA-1. CHAP is also critical for HDA-1 localization to heterochromatin. Specifically, the CHAP zinc finger interacts directly with the HDA-1 argonaute-binding protein 2 (Arb2) domain, and the CHAP AT-hook motifs recognize heterochromatic regions by binding to AT-rich DNA. Our data shed light on the interrelationships among the prototypical heterochromatic features and support a model in which dual recognition by the HP1 chromodomain and the CHAP AT-hooks are required for proper heterochromatin formation.

mentioning

confidence: 99%

Dual chromatin recognition by the histone deacetylase complex HCHC is required for proper DNA methylation in Neurospora crassa

Honda

Bicocca

Gessaman

et al. 2016

“…Alteration of methylation level of the FGF2 promoter. DNA methylation typically leads to transcriptional silencing and H3K9 methylation has been linked with DNA methylation (37,38), with H3K9me3 inducing DNA methylation via activation of various DNA methyltransferases (39,40). As we have observed an alteration in the association of H3K9me3 at the FGF2 promoter, we further assessed the methylation levels at that promoter following neonatal FGF2 exposure.…”

Section: Endogenous Levels Of Methylated Repressive Histone Protein Hmentioning

confidence: 99%

FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3

Chaudhury

Aurbach

Sharma

et al. 2014

Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety-and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes' opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.C hromatin remodeling is a mediator of lasting neural changes in response to experience, such as exposure to stress and drugs of abuse (1-7). Indeed, the interaction of certain modified histones with specific gene promoters has been shown to be an important mechanism of experience-dependent neuroplasticity (8-13). Although numerous studies have examined the impact of the environment on neural epigenetic profiles, relatively few studies have focused on preexisting differences in epigenetic profiles as potential predisposing factors in emotional reactivity. Such studies require the availability of an animal model where difference in "temperament" or propensity for specific affective responses can be reliably predicted and altered. Our laboratory has generated such an animal model that captures vulnerability for "internalizing disorders" vs. "externalizing disorders." Selectively bred high responder (bHR) rats exhibit greater responsiveness to novelty and to drug seeking behavior (externalizing behaviors), whereas selectively bred low responders (bLR) exhibit greater anxiety and depression-like responses (internalizing behaviors) (14, 15). These genetically bred phenotypes amplify behavioral traits observed in outbred animals (16)(17)(18)(19)(20).Several genes have been implicated in modifying these phenotypes, both in the bred and outbr...

“…Although in both animals and fungi, the presence of active TET/JBPs is correlated with DNMT1 (two copies of DNMT1 are present in most basidiomycetes; SI Appendix, Table S1), the rest of their methylation systems show notable differences. In fungi, DNA methylation is widely used to repress or inactivate duplicate copies of genes, thus serving as a mechanism of dosage compensation (27,28). Unlike animals, fungi lack prominent gene body methylation and tend to concentrate their methylation to repetitive sequences (29).…”

Section: Association Between Kdz Superfamily Transposons and Tet/jbpmentioning

confidence: 99%

Lineage-specific expansions of TET/JBP genes and a new class of DNA transposons shape fungal genomic and epigenetic landscapes

Iyer

Zhang

Souza

et al. 2014

TET/JBP dioxygenases oxidize methylpyrimidines in nucleic acids and are implicated in generation of epigenetic marks and potential intermediates for DNA demethylation. We show that TET/JBP genes are lineage-specifically expanded in all major clades of basidiomycete fungi, with the majority of copies predicted to encode catalytically active proteins. This pattern differs starkly from the situation in most other organisms that possess just a single or a few copies of the TET/JBP family. In most basidiomycetes, TET/ JBP genes are frequently linked to a unique class of transposons, KDZ (Kyakuja, Dileera, and Zisupton) and appear to have dispersed across chromosomes along with them. Several of these elements typically encode additional proteins, including a divergent version of the HMG domain. Analysis of their transposases shows that they contain a previously uncharacterized version of the RNase H fold with multiple distinctive Zn-chelating motifs and a unique insert, which are predicted to play roles in structural stabilization and target sequence recognition, respectively. We reconstruct the complex evolutionary history of TET/JBPs and associated transposons as involving multiple rounds of expansion with concomitant lineage sorting and loss, along with several capture events of TET/ JBP genes by different transposon clades. On a few occasions, these TET/JBP genes were also laterally transferred to certain Ascomycota, Glomeromycota, Viridiplantae, and Amoebozoa. One such is an inactive version, calnexin-independence factor 1 (Cif1), from Schizosaccharomyces pombe, which has been implicated in inducing an epigenetically transmitted prion state. We argue that this unique transposon-TET/JBP association is likely to play important roles in speciation during evolution and epigenetic regulation. methylcytosine | fungal evolution | DNA modification | genomic association I ntragenomic conflicts with diverse mobile elements have played a critical role in shaping cellular genomes (1). In eukaryotes, genomic rearrangements mediated by transposons in germ-line cells promote reproductive isolation of organisms and, accordingly, are implicated in speciation events (2, 3). The mobility of transposons has the potential to disrupt genes by insertion as well as to create new genes or to resurrect inactive ones. Indeed, genomic analyses have revealed that transposons are an important source for both regulatory elements and new DNA-binding domains in transcription factors and chromatin proteins across the tree of life (1, 4). Organisms show a diverse array of strategies to counter mobile elements, supporting the idea of a constant arms race between them and genomes. Some of these strategies, such as transcriptional silencing by chromatin modifications (e.g., histone methylation, DNA methylation) and posttranscriptional silencing using components of the RNAi machinery, are widespread across eukaryotes (5). In contrast, processes such as DNA elimination in the macronuclei of ciliates show a restricted phyletic distribution (6). Transpos...