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Abstract The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While gene ontogeny (GO) provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graph multiple GO analyses for comparison. Second, genes from some model systems are not well represented. For example, ∼30% of Caenorhabditis elegans genes are missing from the analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify coexpressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets, and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs, where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations, but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential. phenotypic relevance not found with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat shock genes are unaffected. We also found that two H3K4 methyltransferases, set-2/SET1 and set-16/MLL, had differential responses to survival during stress. set-2/SET1 is specifically required in bacterial responses, whereas set-16/MLL is universally required. These results define a role for SAM in the acute stress-responsive gene expression. Finally, we find that modification of metabolic gene expression correlates with enhanced survival during stress.

The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes. Synapse elimination is a critical process in the maturation of brain circuitry. Here the authors identify a key transcriptional program in Caenorhabditis elegans that directs the elimination of juvenile synapses during developmental circuit rewiring.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1 CC). Alterations in 1 CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in Caenorhabditis elegans , SAMS-1 and SAMS-4 , contribute differently to modification of H3K4me3, gene expression and survival. We find that sams-4 enhances H3K4me3 in heat shocked animals lacking sams-1 , however, sams-1 cannot compensate for sams-4 , which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1 CC function to phenotypes in aging and stress.

A subunit of the ARC/Mediator co-activator complex is a key effector of the SREBP transcription factor during regulation of lipid homeostasis in human cells and Caenorhabditis elegans. The SREBP activation domain directly targets a KIX domain on ARC105/MED15 The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis 1 , 2 . We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms 3 , 4 , 5 . Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes 6 , 7 . We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15 , including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

SREBPs control genes involved in cholesterol/lipid metabolism, membrane synthesis and fat storage. Aberrant SREBP activities have been linked to conditions associated with metabolic syndrome, including insulin resistance, obesity, elevated circulating LDL-C and triglycerides, and nonalcoholic fatty liver diseases. In addition, SREBPs have been implicated in cancer cell proliferation and enveloped viral replication through regulation of membrane synthesis. Therapeutic approaches to block SREBP functions linked to disease states may act through potentiation of SREBP negative regulators such as AMP-activated kinase or the sirtuin, SIRT1, or by inhibiting the proteolytic maturation into the active transcription factor forms. Additionally, cofunctional miRNAs embedded within the SREBP genomic loci (miR-33a/b) may also serve as novel therapeutic targets to ameliorate cardiometabolic diseases. Taken together, aberrant SREBP-linked activities could represent important targets of therapies to limit lipid/cholesterol synthesis or membrane production in metabolic diseases, cancer progression and viral pathogenesis.

TAF II s are conserved components of the TFIID, TFTC and SAGA‐related mRNA transcription complexes. In yeast (y), yTAF II 17 is required broadly for transcription, but various other TAF II s appear to have more specialized functions. It is important to determine how TAF II s contribute to transcription in metazoans, which have larger and more diverse genomes. We have examined TAF II functions in early Caenorhabditis elegans embryos, which can survive without transcription for several cell generations. We show that taf‐10 ( yTAF II 17 ) and taf‐11 ( yTAF II 25 ) are required for a significant fraction of transcription, but apparently are not needed for expression of multiple developmental and other metazoan‐specific genes. In contrast, taf‐5 ( yTAF II 48 ; human TAF II 130 ) seems to be required for essentially all early embryonic mRNA transcription. We conclude that TAF‐10 and TAF‐11 have modular functions in metazoans, and can be bypassed at many metazoan‐specific genes. The broad involvement of TAF‐5 in mRNA transcription in vivo suggests a requirement for either TFIID or a TFTC‐like complex.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in , which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of leads to enhanced heat shock survival and increased lifespan, whereas reducing adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While gene ontogeny (GO) provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graph multiple GO analyses for comparison. Second, genes from some model systems are not well represented. For example, ∼30% of Caenorhabditis elegans genes are missing from the analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify coexpressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets, and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs, where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations, but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential. phenotypic relevance not found with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.