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Lineage-tracing experiments in the mouse show that Lgr6, but not Lgr5, functions as a cancer stem marker in skin squamous cell carcinomas (SCCs). The authors also show that Lgr6-knockout mice are predisposed to SCC development, through a mechanism that includes compensatory upregulation of Lgr5.
High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
Loss of BAF47 destabilizes the BAF complex on chromatin, and reintroduction of BAF47 leads to enhancer activation and Polycomb opposition at bivalent promoters. BAF47 loss affects BAF and PBAF complexes, which have distinct functions in regulation of enhancers and promoters.
Melissa Gymrek and colleagues estimate mutation parameters for each short tandem repeat (STR) in the human genome. They find that local sequence features impact these estimates and they create a framework for measuring constraint at STRs by comparing observed and expected mutation rates, providing a tool for prioritizing pathogenic variants.
Eric Schadt and colleagues present a predictive causal model of the immune component of inflammatory bowel disease through integration of genetic, regulatory and transcriptional data. They prioritize and validate 12 of the top key drivers experimentally in mouse colitis models and human macrophages.
Yoichiro Kamatani and colleagues perform a genome-wide association study (GWAS) for body mass index using data from 173,430 Japanese individuals. They find 85 significant loci, 51 of which are novel, and use trans-ancestral meta-analysis of GWAS from European samples to identify 61 additional new loci.
David Evans, Brent Richards and colleagues carried out a genome-wide association study in 142,487 individuals from the UK Biobank and identified 153 new loci associated with heel bone mineral density. They also conducted in vivo studies that implicated GPC6 and several other genes in osteoporosis.
Danish Saleheen, Benjamin Voight and colleagues perform genome-wide analysis of multi-ancestry cohorts to identify genetic associations with type 2 diabetes (T2D) and coronary heart disease (CHD). They find novel loci and show that 24% of T2D loci are also associated with CHD and that greater genetic risk of T2D increases risk of CHD.
Maria-Elena Torres-Padilla and colleagues use a targeted epigenomic approach to investigate the role of LINE-1 retroelements during early mouse development. Their data suggest that timely activation of LINE-1 regulates global chromatin accessibility and is integral to the mouse developmental program.
Paz Polak, Jaegil Kim, Lior Z. Braunstein and colleagues have identified patterns of genome-wide mutation in certain breast cancers that can be used to identify those with DNA-repair deficiencies that make the tumor more likely to respond to therapies based on PARP inhibitors or platinum. In contrast, oncogenic mutations in several other DNA-repair genes do not generate these patterns.
Elizabeth Perlman and colleagues use genome-wide sequencing, RNA expression, DNA copy number and methylation analyses to characterize the genomic landscape of Wilms tumors. Their integrated analyses implicate two major classes of genetic changes in Wilms tumors that preserve the progenitor state and/or interrupt normal kidney development.
Mathieu Lupien and colleagues analyze data from primary prostate tumors with and without TMPRSS2–ERG (T2E) rearrangements. They find that in T2E tumors, there is a distinct regulatory landscape resulting from the co-option of transcription factors by ERG which causes dependency on NOTCH signaling.
Henry Sucov and colleagues demonstrate substantial natural variation in the capacity of the mouse heart to regenerate after injury and link this to the prevalence of mononuclear diploid cardiomyocytes. They identify Tnni3k as one gene that contributes to the observed variation and validate its role through mouse knockout and zebrafish overexpression studies.
Kevin Brown and colleagues functionally characterize a melanoma risk locus encompassing PARP1, correlating the risk genotype to PARP1 gene expression levels in melanoma cells. They identify an intronic gene-regulatory variant in PARP1 and find that PARP1 can promote cell proliferation and rescue oncogene-induced senescence, likely through MITF.
Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating the expression of R-spondin1 and Sprouty1, respectively.
Peter Balint-Kurti, Qin Yang and colleagues report that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase, is a gene within the quantitative trait locus qMdr9.02, which confers resistance to southern leaf blight and gray leaf spot. Their findings suggest that resistance might be caused by differences in levels of lignin and other metabolites in the phenylpropanoid pathway.
Terence Capellini, David Kingsley and colleagues use transgenic mice to show that a Gdf5 enhancer (termed GROW1) is required for normal bone length. They suggest that a common variant at the human GROW1 enhancer was under selection in human populations and also contributes to arthritis susceptibility.
Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.
Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.
Damian Smedley and colleagues report the phenotypic characterization of the first 3,328 genes by the International Mouse Phenotyping Consortium. They develop new mouse models based on genes known to be associated with human mendelian diseases and identify potential disease-associated genes with little or no previous functional annotation.