Life Sciences Research for Lifelong Health

Peter Fraser

Please note, Peter now also leads a research group at Florida State University. Visit his page there for full details of his current research.

Research Summary

Dynamic changes in chromatin and chromosome architecture regulates patterns of cellular gene expression during differentiation and development, or in response to environmental signals. Our research looks at various levels of chromatin, chromosome and nuclear structure, from individual nucleosome modifications to the dynamic 3D structure of chromosomes and their inter-relationships in the nucleus and how they affect genome functions.

Latest Publications

Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions.
Schoenfelder S, Javierre BM, Furlan-Magaril M, Wingett SW, Fraser P

The three-dimensional organization of the genome is linked to its function. For example, regulatory elements such as transcriptional enhancers control the spatio-temporal expression of their target genes through physical contact, often bridging considerable (in some cases hundreds of kilobases) genomic distances and bypassing nearby genes. The human genome harbors an estimated one million enhancers, the vast majority of which have unknown gene targets. Assigning distal regulatory regions to their target genes is thus crucial to understand gene expression control. We developed Promoter Capture Hi-C (PCHi-C) to enable the genome-wide detection of distal promoter-interacting regions (PIRs), for all promoters in a single experiment. In PCHi-C, highly complex Hi-C libraries are specifically enriched for promoter sequences through in-solution hybrid selection with thousands of biotinylated RNA baits complementary to the ends of all promoter-containing restriction fragments. The aim is to then pull-down promoter sequences and their frequent interaction partners such as enhancers and other potential regulatory elements. After high-throughput paired-end sequencing, a statistical test is applied to each promoter-ligated restriction fragment to identify significant PIRs at the restriction fragment level. We have used PCHi-C to generate an atlas of long-range promoter interactions in dozens of human and mouse cell types. These promoter interactome maps have contributed to a greater understanding of mammalian gene expression control by assigning putative regulatory regions to their target genes and revealing preferential spatial promoter-promoter interaction networks. This information also has high relevance to understanding human genetic disease and the identification of potential disease genes, by linking non-coding disease-associated sequence variants in or near control sequences to their target genes.

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Journal of visualized experiments : JoVE, , 1940-087X, , 2018

PMID: 30010637

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.
Choy MK, Javierre BM, Williams SG, Baross SL, Liu Y, Wingett SW, Akbarov A, Wallace C, Freire-Pritchett P, Rugg-Gunn PJ, Spivakov M, Fraser P, Keavney BD

Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We also show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. These findings indicate that regulatory elements in hESC-CMs identified by our approach control gene expression involved in ventricular conduction and rhythm of the heart. The study of promoter interactions in other hESC-derived cell types may be of utility in functional investigation of GWAS-associated regions.

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Nature communications, 9, 2041-1723, 2526, 2018

PMID: 29955040

The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.
Beekman R, Chapaprieta V, Russiñol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens JHA, Duran-Ferrer M, Kulis M, Serra F, Javierre BM, Wingett SW, Clot G, Queirós AC, Castellano G, Blanc J, Gut M, Merkel A, Heath S, Vlasova A, Ullrich S, Palumbo E, Enjuanes A, Martín-García D, Beà S, Pinyol M, Aymerich M, Royo R, Puiggros M, Torrents D, Datta A, Lowy E, Kostadima M, Roller M, Clarke L, Flicek P, Agirre X, Prosper F, Baumann T, Delgado J, López-Guillermo A, Fraser P, Yaspo ML, Guigó R, Siebert R, Martí-Renom MA, Puente XS, López-Otín C, Gut I, Stunnenberg HG, Campo E, Martin-Subero JI

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.

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Nature medicine, , 1546-170X, , 2018

PMID: 29785028

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Keywords

3d genome
genome function

Group Members

Latest Publications

Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions.

Schoenfelder S, Javierre BM, Furlan-Magaril M

Journal of visualized experiments : JoVE
1940-087X: (2018)

PMID: 30010637

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.

Choy MK, Javierre BM, Williams SG

Nature communications
9 2041-1723:2526 (2018)

PMID: 29955040

The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.

Beekman R, Chapaprieta V, Russiñol N

Nature medicine
1546-170X: (2018)

PMID: 29785028

Allele-specific control of replication timing and genome organization during development.

Rivera-Mulia JC, Dimond A, Vera D

Genome research
1549-5469: (2018)

PMID: 29735606

Capturing Three-Dimensional Genome Organization in Individual Cells by Single-Cell Hi-C.

Nagano T, Wingett SW, Fraser P

Methods in molecular biology (Clifton, N.J.)
1654 1940-6029:79-97 (2017)

PMID: 28986784

Chromosome contacts in activated T cells identify autoimmune disease candidate genes.

Burren OS, Rubio García A, Javierre BM

Genome biology
18 1474-760X:165 (2017)

PMID: 28870212

Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation.

Rubin AJ, Barajas BC, Furlan-Magaril M

Nature genetics
1546-1718: (2017)

PMID: 28805829

Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Petersen R, Lambourne JJ, Javierre BM

Nature communications
8 2041-1723:16058 (2017)

PMID: 28703137

Cell-cycle dynamics of chromosomal organization at single-cell resolution.

Nagano T, Lubling Y, Várnai C

Nature
547 1476-4687:61-67 (2017)

PMID: 28682332