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

Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.
Sima J, Chakraborty A, Dileep V, Michalski M, Klein KN, Holcomb NP, Turner JL, Paulsen MT, Rivera-Mulia JC, Trevilla-Garcia C, Bartlett DA, Zhao PA, Washburn BK, Nora EP, Kraft K, Mundlos S, Bruneau BG, Ljungman M, Fraser P, Ay F, Gilbert DM

The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these "early replication control elements" (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.

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Cell, , 1097-4172, , 2018

PMID: 30595451

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.
Koohy H, Bolland DJ, Matheson LS, Schoenfelder S, Stellato C, Dimond A, Várnai C, Chovanec P, Chessa T, Denizot J, Manzano Garcia R, Wingett SW, Freire-Pritchett P, Nagano T, Hawkins P, Stephens L, Elderkin S, Spivakov M, Fraser P, Corcoran AE, Varga-Weisz PD

Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice.

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Genome biology, 19, 1474-760X, 126, 2018

PMID: 30180872

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

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Keywords

3d genome
genome function

Group Members

Latest Publications

Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.

Sima J, Chakraborty A, Dileep V

Cell
1097-4172: (2018)

PMID: 30595451

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