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This issue highlights a range of genetic techniques and cell biological models required to begin to understand the levels of long-range regulation of gene expression as it occurs during cell differentiation. Explanations based on the specificity of covalent modifications and binding interactions intersect with evidence for conjectured mechanisms of topological loop creation and maintenance by transcription and motile protein activities.
Regulation of epigenetic factors through their recruitment to specific genomic regions is still poorly understood. A recent study demonstrates a global mechanism of tethering Polycomb group (PcG) proteins through sequence-specific DNA-binding factors.
The functional role of repetitive elements in mammalian genomes is still largely unexplored. A new study provides evidence that LINE-1 retrotransposons regulate chromatin dynamics and are essential for normal embryonic development in mice.
A new study uses a Hi-C technique to demonstrate that condensin has a major role in remodeling interphase chromatin into mitotic chromosomes. This study provides insight into the mechanism whereby a centimeters-long DNA molecule is folded into a micrometers-long rod-shaped chromosome.
Steven Gazal, Alkes Price and colleagues extend stratified LD score regression to continuous annotations. They analyze summary statistics from 56 complex diseases and traits and find that SNPs with low levels of linkage disequilibrium have larger per-SNP heritability, consistent with the action of negative selection on deleterious variants that affect complex traits.
Kevin Yip and colleagues report a method for determining the target genes of enhancers in specific cells and tissues by combining global trends across many samples with sample-specific information, and considering the joint effect of multiple enhancers. They apply their method to reconstruct enhancer–target networks in 935 samples of human primary cells, tissues and cell lines.
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.
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.
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.
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.
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.
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.
Robert Graham and colleagues carried out a GWAS meta-analysis for Parkinson's disease (PD) and report 17 new risk loci. Their analyses support a key role for autophagy and lysosomal biology in PD risk.
Greg Gibson and colleagues integrate summary-level GWAS and eQTL data with RNA-seq data from a cohort of pediatric Crohn's disease and report transcriptional risk scores that identify patients who will progress to complicated disease. Their dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion or protection.
Adam Rubin, Brook Barajas, Mayra Furlan-Magaril and colleagues studied dynamic chromatin across the genome of differentiating human skin keratinocytes, identifying both stable and reorganizing classes of transcriptional enhancers.
Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt and colleagues report that mutations in OSGEP, TP53RK, TPRKB and LAGE3, genes encoding KEOPS-complex subunits, cause Galloway–Mowat syndrome, a recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Functional studies suggest that the phenotypes result from impaired protein translation, thus leading to endoplasmic reticulum stress and apoptosis.
Stefan Mundlos, Darío Lupiáñez and colleagues investigate CNVs involving the regulatory landscape of IHH (Indian hedgehog), which cause craniosynostosis and synpolydactyly. Using genetic manipulation in mice, they show that Ihh is regulated by at least nine enhancers with individual tissue specificities and that duplications in this region can cause dose-dependent upregulation and also misexpression of Ihh.
Doris Wagner and colleagues define Polycomb response elements (PREs) that direct the placement of Polycomb repressive complex 2 (PRC2) at developmental genes in Arabidopsis. They identify transcription factor families that bind to PREs, physically interact with and recruit PRC2, and are required for gene silencing in vivo.
Frank Uhlmann and colleagues use chromosome conformation capture (Hi-C) to study mitotic chromosome condensation in the fission yeast Schizosaccharomyces pombe, reporting that small chromatin domains in interphase are replaced by fewer and larger domains in mitosis. They show that condensin sets up longer-range DNA interactions that compact and individualize chromosomes while also restraining local chromatin contacts.
