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

Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition.
Novo CL, Javierre BM, Cairns J, Segonds-Pichon A, Wingett SW, Freire-Pritchett P, Furlan-Magaril M, Schoenfelder S, Fraser P, Rugg-Gunn PJ

Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs). We found that SEs form complex, spatial networks in which individual SEs contact multiple promoters, and a rewiring of promoter-SE interactions occurs between pluripotent states. We also show that long-range promoter-SE interactions are more prevalent in ESCs than in epiblast stem cells (EpiSCs) or Nanog-deficient ESCs. We conclude that SEs form cell-type-specific interaction networks that are partly dependent on core transcription factors, thereby providing insights into the gene regulatory organization of pluripotent cells.

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Cell reports, 22, 2211-1247, 2615-2627, 2018

PMID: 29514091

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures.
Comoglio F, Park HJ, Schoenfelder S, Barozzi I, Bode D, Fraser P, Green AR

Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra- and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO.

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Genome research, , 1549-5469, , 2018

PMID: 29429976

Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins.
Wutz G, Várnai C, Nagasaka K, Cisneros DA, Stocsits RR, Tang W, Schoenfelder S, Jessberger G, Muhar M, Hossain MJ, Walther N, Koch B, Kueblbeck M, Ellenberg J, Zuber J, Fraser P, Peters JM

Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.

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The EMBO journal, , 1460-2075, , 2017

PMID: 29217591

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Keywords

3d genome
genome function

Group Members

Latest Publications

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

Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.

Siersbæk R, Madsen JGS, Javierre BM

Molecular cell
66 1097-4164:420-435.e5 (2017)

PMID: 28475875

GOTHiC, a probabilistic model to resolve complex biases and to identify real interactions in Hi-C data.

Mifsud B, Martincorena I, Darbo E

PloS one
12 1932-6203:e0174744 (2017)

PMID: 28379994

Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

Freire-Pritchett P, Schoenfelder S, Várnai C

eLife
6 2050-084X: (2017)

PMID: 28332981