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Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer–promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci. Multiple regulatory elements distant from their targets on the linear genome can influence gene expression through chromatin looping. Here, the authors report an improved chromosome conformation capture approach that can be used to identify long-range chromatin interactions in cancer risk loci.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL. The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.

Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P- specific null mice. P2 -null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1 -null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2 -null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1 -transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2 -derived gene-products containing frizzled-like sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2 -transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2- null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

Richard Houlston and colleagues report results of a genome-wide association study of chronic lymphocytic leukemia. They validate several new susceptibility loci for this disease, including variants near POT1 , TERC and TERT . Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10 −9 ), 4q26 (rs6858698, P = 3.07 × 10 −9 ), 6q25.2 ( IPCEF1 , rs2236256, P = 1.50 × 10 −10 ) and 7q31.33 ( POT1 , rs17246404, P = 3.40 × 10 −8 ). Additionally, we identified a promising association at 5p15.33 ( CLPTM1L , rs31490, P = 1.72 × 10 −7 ) and validated recently reported putative associations at 5p15.33 ( TERT , rs10069690, P = 1.12 × 10 −10 ) and 8q22.3 (rs2511714, P = 2.90 × 10 −9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 ( NCK1 , rs11715604, P  = 1.60 × 10 −9 ) with opposing effects between CLL ( P  = 1.97 × 10 −8 ) and HL ( P  = 3.31 × 10 −3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 ( P  = 1.84 × 10 −12 ) was associated with increased CLL and HL risk ( P  = 4.68 × 10 −12 ), and reduced MM risk ( P  = 1.12 × 10 −2 ), and Gly70 in HLA-DQB1 ( P  = 3.15 × 10 −10 ) showed opposing effects between CLL ( P  = 3.52 × 10 −3 ) and HL ( P  = 3.41 × 10 −9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P =5.04 × 10 −13 ), 1q42.13 (rs41271473, P =1.06 × 10 −10 ), 4q24 (rs71597109, P =1.37 × 10 −10 ), 4q35.1 (rs57214277, P =3.69 × 10 −8 ), 6p21.31 (rs3800461, P =1.97 × 10 −8 ), 11q23.2 (rs61904987, P =2.64 × 10 −11 ), 18q21.1 (rs1036935, P =3.27 × 10 −8 ), 19p13.3 (rs7254272, P =4.67 × 10 −8 ) and 22q13.33 (rs140522, P =2.70 × 10 −9 ). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.