Caenorhabditis elegans establishes germline versus soma by balancing inherited histone methylation.

Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In Caenorhabditis elegans, this reprogramming is mediated by the H3K4me2 demethylase SPR-5 and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase MES-4 maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathways. We found that the developmental delay of spr-5; met-2 mutant progeny is associated with ectopic H3K36me3 and the ectopic expression of MES-4-targeted germline genes in somatic tissues. Furthermore, the developmental delay is dependent upon MES-4 and the H3K4 methyltransferase, SET-2. We propose that MES-4 prevents crucial germline genes from being repressed by antagonizing maternal spr-5; met-2 reprogramming. Thus, the balance of inherited histone modifications is necessary to distinguish germline versus soma and prevent developmental delay.This article has an associated 'The people behind the papers' interview.

Centrocortin potentiates co-translational localization of its mRNA to the centrosome via dynein.

Centrosomes rely upon proteins within the pericentriolar material to nucleate and organize microtubules. Several mRNAs also reside at centrosomes, although less is known about how and why they accumulate there. We previously showed that local Centrocortin (Cen) mRNA supports centrosome separation, microtubule organization, and viability in Drosophila embryos. Here, using Cen mRNA as a model, we examine mechanisms of centrosomal mRNA localization. We find that while the Cen N'-terminus is sufficient for protein enrichment at centrosomes, multiple domains cooperate to concentrate Cen mRNA at this location. We further identify an N'-terminal motif within Cen that is conserved among dynein cargo adaptor proteins and test its contribution to RNA localization. Our results support a model whereby Cen protein enables the accumulation of its own mRNA to centrosomes through a mechanism requiring active translation, microtubules, and the dynein motor complex. Taken together, our data uncover the basis of translation-dependent localization of a centrosomal RNA required for mitotic integrity.

A missense SNP in the tumor suppressor SETD2 reduces H3K36me3 and mitotic spindle integrity in Drosophila.

Mutations in SETD2 are among the most prevalent drivers of renal cell carcinoma (RCC). We identified a novel single nucleotide polymorphism (SNP) in SETD2, E902Q, within a subset of RCC patients, which manifests as both an inherited or tumor-associated somatic mutation. To determine if the SNP is biologically functional, we used CRISPR-based genome editing to generate the orthologous mutation within the Drosophila melanogaster Set2 gene. In Drosophila, the homologous amino acid substitution, E741Q, reduces H3K36me3 levels comparable to Set2 knockdown, and this loss is rescued by reintroduction of a wild-type Set2 transgene. We similarly uncovered significant defects in spindle morphogenesis, consistent with the established role of SETD2 in methylating α-Tubulin during mitosis to regulate microtubule dynamics and maintain genome stability. These data indicate the Set2 E741Q SNP affects both histone methylation and spindle integrity. Moreover, this work further suggests the SETD2 E902Q SNP may hold clinical relevance.