Volume 41 Issue 8, August 2009

Chromatin marks, including histone modifications and variants, have become important tools for characterizing epigenomes, yet how they might interact with one another to facilitate gene expression and regulation has remained unclear. A new study maps unstable nucleosomes containing both H3.3 and H2A.Z histone variants to human promoters and regulatory elements and suggests that transient occupancy by double-variant nucleosomes is a general feature of eukaryotic gene regulation.

A new study reports the first mouse model for ATR-mutated Seckel syndrome. The mice show phenotypes recapitulating the human disorder and provide insights into how reduced ATR function affects normal embryonic development by increasing replicative stress, ultimately resulting in an accelerated aging phenotype postnatally.

Two new reports highlight the power of genome-wide association (GWA) studies to guide the functional annotation of genetic variants contributing to common diseases. The studies show that a common risk variant for colorectal cancer on chromosome 8q24 affects TCF4 binding to an enhancer that interacts with the MYC promoter, providing a mechanistic explanation for the association of this variant with disease risk.

Christine Skibola and colleagues report a genome-wide association study for three subtypes of non-Hodgkin lymphoma. They report an association of a variant in the PSORS1 region in the MHC to increased risk of follicular lymphoma.

Daniel Gudbjartsson and colleagues report a genome-wide association study for atrial fibrillation, a condition associated with increased risk of stroke. They report a variant in ZFHX3 associated with atrial fibrillation as well as ischemic stroke.

Emelia Benjamin and colleagues report a meta-analysis of genome-wide association study data for atrial fibrillation, a condition associated with stroke and heart failure, in five European community-based cohorts of the CHARGE consortium. They report an association in ZFHX3 to atrial fibrillation, with replication in an independent cohort from the German AF Network.

Matthew Freedman and colleagues show that a region on 8q24 associated with colorectal cancer risk functions as an enhancer and undergoes long-range interactions with MYC. They further show that alleles at the risk-associated SNP bind differentially to TCF7L2, a transcription factor in the Wnt pathway.

Lauri Aaltonen and colleagues show that a region on 8q24 associated with colorectal cancer risk functions as an enhancer and that the risk allele at this locus binds with higher affinity to the Wnt-regulated transcription factor TCF4 (also called TCF7L2), conferring enhanced responsiveness to Wnt signaling.

Oscar Fernandez-Capetillo and colleagues report a mouse model of the human Seckel syndrome characterized by a deficiency in ATR. The Seckel mice show high levels of replicative stress during embryogenesis, and the adults show premature aging.

Richard Houlston, Melissa Bondy and colleagues identify variants at five loci associated with glioma susceptibility, providing insights into the etiology of this primary brain tumor. The risk loci include common variants near TERT, CDKN2A-CDKN2B and RTEL1.

Margaret Wrensch and colleagues report a genome-wide association and replication study for high-grade glioma. They show that common variants in the CDKN2B and RTEL1 regions are associated with risk of this aggressive brain tumor.

Simon Stacey and colleagues report several new susceptibility variants for basal cell carcinoma, including coding variants in KRT5, a variant at 9p21 near CDKN2A and CDKN2B and a variant at 7q32 near KLF14. The latter is an imprinted gene, and the effect at this locus is dependent on the parental origin of the risk allele.

Timothy Spector, Mario Falchi and colleagues report a genome-wide association study for development of cutaneous nevi, the strongest known risk factor for cutaneous melanoma. They report two loci associated with nevus count, and show these loci are also associated with susceptibility to melanoma.

Timothy Bishop and colleagues from GenoMEL present a genome-wide association study for melanoma. They report three loci associated with susceptibility to melanoma, of which two were previously associated with pigmentation.

Gudmar Thorleifsson and colleagues report a genome-wide association study for kidney stones. They report common variants in CLDN14 associated with increased risk of kidney stone disease.

Christine Seidman and colleagues report that 1% of individuals with sporadic non-syndromic tetralogy of Fallot show copy number gains or losses at chromosome 1q21.1. They also report copy number changes at other loci that likely contribute to the etiology of this congenital heart malformation.

Klaus Schwarz and colleagues show that mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoetic anemia type II, a rare disease marked by defective cytokinesis in erythroblasts and membrane abnormalities in nucleated and peripheral red blood cells.

Gary Felsenfeld and colleagues examine the distribution of H3.3- and H2A.Z-containing nucleosomes genome-wide. They find that regions at transcription start sites of active genes, which were thought to be “nucleosome-free regions,” are enriched for unstable H2A.Z and H3.3 double-variant nucleosomes. These results suggest that double-variant nucleosomes may be important in the regulation of transcription factor access to promoters.

Kokubu and colleagues have developed a method for mapping cis-regulatory elements in the mouse using targeted integration of the Sleeping Beauty transposon. This method also gives researchers the ability to generate targeted deletions for testing loss-of-function effects.