Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression.

Transcriptional cofactors are essential for proper embryonic development. One such cofactor in Drosophila, Degringolade (Dgrn), encodes a RING finger/E3 ubiquitin ligase. Dgrn and its mammalian ortholog RNF4 are SUMO-targeted ubiquitin ligases (STUbLs). STUbLs bind to SUMOylated proteins via their SUMO interaction motif (SIM) domains and facilitate substrate ubiquitylation. In this study, we show that Dgrn is a negative regulator of the repressor Hairy and its corepressor Groucho (Gro/transducin-like enhancer (TLE)) during embryonic segmentation and neurogenesis, as dgrn heterozygosity suppresses Hairy mutant phenotypes and embryonic lethality. Mechanistically Dgrn functions as a molecular selector: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its corepressor Gro, without affecting the recruitment of its other cofactors or the stability of Hairy. Concomitantly, Dgrn specifically targets SUMOylated Gro for sequestration and antagonizes Gro functions in vivo. Our findings suggest that by targeting SUMOylated Gro, Dgrn serves as a molecular switch that regulates cofactor recruitment and function during development. As Gro/TLE proteins are conserved universal corepressors, this may be a general paradigm used to regulate the Gro/TLE corepressors in other developmental processes.

The histone H3K36 methyltransferase MES-4 acts epigenetically to transmit the memory of germline gene expression to progeny.

Methylation of histone H3K36 in higher eukaryotes is mediated by multiple methyltransferases. Set2-related H3K36 methyltransferases are targeted to genes by association with RNA Polymerase II and are involved in preventing aberrant transcription initiation within the body of genes. The targeting and roles of the NSD family of mammalian H3K36 methyltransferases, known to be involved in human developmental disorders and oncogenesis, are not known. We used genome-wide chromatin immunoprecipitation (ChIP) to investigate the targeting and roles of the Caenorhabditis elegans NSD homolog MES-4, which is maternally provided to progeny and is required for the survival of nascent germ cells. ChIP analysis in early C. elegans embryos revealed that, consistent with immunostaining results, MES-4 binding sites are concentrated on the autosomes and the leftmost approximately 2% (300 kb) of the X chromosome. MES-4 overlies the coding regions of approximately 5,000 genes, with a modest elevation in the 5' regions of gene bodies. Although MES-4 is generally found over Pol II-bound genes, analysis of gene sets with different temporal-spatial patterns of expression revealed that Pol II association with genes is neither necessary nor sufficient to recruit MES-4. In early embryos, MES-4 associates with genes that were previously expressed in the maternal germ line, an interaction that does not require continued association of Pol II with those loci. Conversely, Pol II association with genes newly expressed in embryos does not lead to recruitment of MES-4 to those genes. These and other findings suggest that MES-4, and perhaps the related mammalian NSD proteins, provide an epigenetic function for H3K36 methylation that is novel and likely to be unrelated to ongoing transcription. We propose that MES-4 transmits the memory of gene expression in the parental germ line to offspring and that this memory role is critical for the PGCs to execute a proper germline program.

Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3.

Cone degeneration (cd ) is an autosomal recessive canine disease that occurs naturally in the Alaskan Malamute and German Shorthaired Pointer breeds. It is phenotypically similar to human achromatopsia, a heterogeneous autosomal recessive disorder associated with three distinct loci. Both the canine disease and its human counterparts are characterized by day-blindness and absence of retinal cone function in adults. We report linkage of the canine cd locus to marker C29.002 on canine chromosome 29 at recombination fraction theta = 0.0 with a maximum LOD score of 24.68 in a series of informative outbred pedigrees derived from cd-affected Alaskan Malamutes. Conserved gene order between CFA29 and the long arm of human chromosome 8 argued for homology between the cd locus and the human achromatopsia locus, ACHM3, at 8q21-22. The canine homolog of the cyclic nucleotide-gated channel beta-subunit gene (CNGB3), responsible for the human ACHM3 disease phenotype, was mapped within the zero-recombination interval for the cd locus. A deletion removing all exons of canine CNGB3 was identified in cd-affected Alaskan Malamute-derived dogs. A missense mutation in exon 6 (D262N, nucleotide 784) within a conserved region of the same gene was detected in German Shorthaired Pointers affected with an allelic disorder. Identification of these canine disorders as homologs of human ACHM3 underscores the power of recent developments in canine genomics, and provides a valuable system for exploring disease mechanisms and evaluating potential therapeutic measures in disorders of cone photoreceptors.