Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ∼200 HSA21 genes encoding proteins have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified 10 HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1). We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.

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Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21 st chromosome (HSA21). Only a few of ~200 HSA21 genes encoding protein have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-offunction mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified ten HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1

One of the most frequently genetically altered chromatin modifiers in melanoma is the Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which methylates lysine 27 on histone 3 (H3K27me3), a chromatin mark associated with transcriptional repression. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641). The oncogenic role of EZH2 in melanoma has previously been determined; however, its downstream oncogenic mechanisms remain underexplored. Here, we found that in genetically engineered mouse models, expression of Ezh2Y641F causes up-regulation of a subset of interferon-regulated genes in melanoma cells, suggesting a potential role of the immune system in the pathogenesis of these mutations. Expression of these interferon genes was not a result of changes in H3K27me3, but through a direct and non-canonical interaction between Ezh2 and Signal Transducer And Activator of Transcription 3 (Stat3). We found that Ezh2 directly binds Stat3, and that in the presence of Ezh2Y641F mutant, Stat3 protein is hypermethylated. Expression of Stat3 was required to maintain an anti-tumor immune response and its depletion resulted in faster melanoma progression and disease recurrence. Molecularly, Stat3 and Ezh2 bind together at many genomic loci, and, in association with the rest of the PRC2 complex, repress gene expression. These results suggest that one of the oncogenic mechanisms of Ezh2-mediated melanomagenesis is through evasion of the anti-tumor immune response, and that the immunomodulatory properties of Stat3 are context dependent.