SET-9 and SET-26 impact transgenerational epigenetic inheritance and germline mortality through their PHD finger and SET domains
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE245982 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:Transgenerational epigenetic inheritance (TEI), the transmission of epigenetic states between generations, has been observed in complex organisms ranging from plants to nematode worms, insects and mammals. One form of TEI that has been robustly studied is the inheritance of gene silencing. In Caenorhabditis elegans transgenerational gene silencing can be partitioned into three phases: the initiation of silencing, establishment of a heritable silencing signal within the parent individuals, and maintenance of this silencing signal within subsequent generations. Silencing involves nuclear and cytoplasmic components, and most genes involved in the process are linked to small RNA processing pathways. To date, two predicted histone methyltransferases have been implicated in the establishment of TEI, set-25 and set-32. Here, we demonstrate that the closely related paralogues set-9 and set-26 function in establishment and maintenance of TEI. We also identify a third related gene that lacks any predicted ordered domains; we name this gene intrinsically disordered protein-1 (idp-1). Strikingly, idp-1 also plays a role in establishment of TEI. SET-9 and SET-26 each contain a PHD finger and a SET domain. We show that the SET domains of SET-9 and SET-26 likely have no histone lysine methyltransferase activity, but that the PHD fingers bind trimethylated histone 3 lysine 4 (H3K4me3) in the absence of adjacent histone marks. We demonstrate that despite modelling data that suggests that set-9 and set-26 lack histone lysine methyltransferase activity, the function of both genes in TEI requires their PHD finger and SET domains. Our data confirm that the SET domain is functional and identifies three new chromatin factors required for epigenetic inheritance.
2024-12-31 | GSE245980 | GEO
Project description:Transgenerational epigenetic inheritance (TEI), the transmission of epigenetic states between generations, has been observed in complex organisms ranging from plants to nematode worms, insects and mammals. One form of TEI that has been robustly studied is the inheritance of gene silencing. In Caenorhabditis elegans transgenerational gene silencing can be partitioned into three phases: the initiation of silencing, establishment of a heritable silencing signal within the parent individuals, and maintenance of this silencing signal within subsequent generations. Silencing involves nuclear and cytoplasmic components, and most genes involved in the process are linked to small RNA processing pathways. To date, two predicted histone methyltransferases have been implicated in the establishment of TEI, set-25 and set-32. Here, we demonstrate that the closely related paralogues set-9 and set-26 function in establishment and maintenance of TEI. We also identify a third related gene that lacks any predicted ordered domains; we name this gene intrinsically disordered protein-1 (idp-1). Strikingly, idp-1 also plays a role in establishment of TEI. SET-9 and SET-26 each contain a PHD finger and a SET domain. We show that the SET domains of SET-9 and SET-26 likely have no histone lysine methyltransferase activity, but that the PHD fingers bind trimethylated histone 3 lysine 4 (H3K4me3) in the absence of adjacent histone marks. We demonstrate that despite modelling data that suggests that set-9 and set-26 lack histone lysine methyltransferase activity, the function of both genes in TEI requires their PHD finger and SET domains. Our data confirm that the SET domain is functional and identifies three new chromatin factors required for epigenetic inheritance.
2024-12-31 | GSE245981 | GEO
Project description:SET-9 and SET-26 impact transgenerational epigenetic inheritance and germline mortality through their PHD finger and SET domains
| PRJNA1030917 | ENA
Project description:SET-9 and SET-26 impact transgenerational epigenetic inheritance and germline mortality through their PHD finger and SET domains [RNA-Seq ]
| PRJNA1030919 | ENA
Project description:SET-9 and SET-26 impact transgenerational epigenetic inheritance and germline mortality through their PHD finger and SET domains [small RNA-seq]
| PRJNA1030918 | ENA
Project description:Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.
| S-EPMC4109920 | biostudies-literature
Project description:The plant homeodomain (PHD) fingers are among the largest family of epigenetic domains, first characterized as readers of methylated H3K4. Readout of histone post-translational modifications by PHDs has been the subject of intense investigation; however, less is known about the recognition of secondary structure features within the histone tail itself. We solved the crystal structure of the PHD finger of the bromodomain adjacent to zinc finger 2A [BAZ2A, also known as TIP5 (TTF-I/interacting protein 5)] in complex with unmodified N-terminal histone H3 tail. The peptide is bound in a helical folded-back conformation after K4, induced by an acidic patch on the protein surface that prevents peptide binding in an extended conformation. Structural bioinformatics analyses identify a conserved Asp/Glu residue that we name 'acidic wall', found to be mutually exclusive with the conserved Trp for K4Me recognition. Neutralization or inversion of the charges at the acidic wall patch in BAZ2A, and homologous BAZ2B, weakened H3 binding. We identify simple mutations on H3 that strikingly enhance or reduce binding, as a result of their stabilization or destabilization of H3 helicity. Our work unravels the structural basis for binding of the helical H3 tail by PHD fingers and suggests that molecular recognition of secondary structure motifs within histone tails could represent an additional layer of regulation in epigenetic processes.
| S-EPMC5415848 | biostudies-literature
Project description:C. elegans SET-9 and SET-26 are highly homologous paralogs that share redundant functions in germline development, but SET-26 alone plays a key role in longevity and heat stress response. Whereas SET-26 is broadly expressed, SET-9 is only detectable in the germline, which likely accounts for their different biological roles. SET-9 and SET-26 bind to H3K4me3 with adjacent acetylation marks in vitro and in vivo. In the soma, SET-26 acts through DAF-16 to modulate longevity. In the germline, SET-9 and SET-26 restrict H3K4me3 domains around SET-9 and SET-26 binding sites, and regulate the expression of specific target genes, with critical consequence on germline development. SET-9 and SET-26 are highly conserved and our findings provide new insights into the functions of these H3K4me3 readers in germline development and longevity.
| S-EPMC6010342 | biostudies-literature
Project description:Plant homeodomain (PHD) zinc fingers are histone reader domains that are often associated with human diseases. Despite this, they constitute a poorly targeted class of readers, suggesting low ligandability. Here, we describe a successful fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B as model systems. We validated a pool of in silico fragments both biophysically and structurally and solved the first crystal structures of PHD zinc fingers in complex with fragments bound to an anchoring pocket at the histone binding site. The best-validated hits were found to displace a histone H3 tail peptide in competition assays. This work identifies new chemical scaffolds that provide suitable starting points for future ligand optimization using structure-guided approaches. The demonstrated ligandability of the PHD reader domains could pave the way for the development of chemical probes to drug this family of epigenetic readers.
| S-EPMC5913730 | biostudies-literature
Project description:Although the plant homeodomain (PHD) finger superfamily is known for its site-specific readouts of histone tails, the origins of the mechanistic differences in histone H3 readout by different PHD subtypes remain less clear. We show that sequences containing the xCDxCDx motif in the PHD treble clef (xCDxCDx-PHD) constitute a distinct subtype, based on the following observations: (i) the amino acid composition of the binding site is strikingly different from other subtypes due to position-specific enrichment of negatively charged and bulky nonpolar residues, (ii) the binding site positions are mutually and positively correlated, and this correlation is absent in other subtypes, and (iii) there are only small structural deviations, despite low sequence similarity. The xCDxCDx-PHD constitutes ∼20% of the PHD family, and the double PHD fingers (DPFs) are 10% of the total number of xCDxCDx-PHDs. This subtype originated early in the evolution of eukaryotes but has diversified within the metazoan lineage. Despite sequence diversification, the positions of the enriched nonpolar residues, in particular, show very small structural deviations, suggesting critical contributions of nonpolar residues in the binding mechanism of this subtype. Using mutagenesis, we probed the contributions of the binding-site positions enriched in nonpolar residues in four xCDxCDx-PHD proteins and found that they contribute to the tight packing of the H3 residues. This effect may potentially be exploited, as we observed affinity enhancement upon substituting a bulky nonpolar residue at the same binding site in another histone reader. Overall, we present a detailed characterization of PHD subtypes.
| S-EPMC6048597 | biostudies-literature