Life Sciences Research for Lifelong Health
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Sarah Elderkin

Research Summary

Gene regulationOur lab is interested in understanding how genome architecture and epigenetic processes control gene expression to regulate stem cell self-renewal and differentiation. In particular, work in the lab is centred on understanding the contribution of the Polycomb Repressive Complexes to these processes.

We study the role of these essential regulators during early development and in tissue homeostasis and regeneration, using state of the art molecular and genomic technologies, both in model stem cell systems and in vivo.

 

Latest Publications

Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression.
Kar G, Kim JK, Kolodziejczyk AA, Natarajan KN, Torlai Triglia E, Mifsud B, Elderkin S, Marioni JC, Pombo A, Teichmann SA

Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.

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Nature communications, 8, 2041-1723, 36, 2017

PMID: 28652613

The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells.
Novo CL, Tang C, Ahmed K, Djuric U, Fussner E, Mullin NP, Morgan NP, Hayre J, Sienerth AR, Elderkin S, Nishinakamura R, Chambers I, Ellis J, Bazett-Jones DP, Rugg-Gunn PJ

An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells.

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Genes & development, , 1549-5477, , 2016

PMID: 27125671

Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.
Schoenfelder S, Sugar R, Dimond A, Javierre BM, Armstrong H, Mifsud B, Dimitrova E, Matheson L, Tavares-Cadete F, Furlan-Magaril M, Segonds-Pichon A, Jurkowski W, Wingett SW, Tabbada K, Andrews S, Herman B, LeProust E, Osborne CS, Koseki H, Fraser P, Luscombe NM, Elderkin S

The Polycomb repressive complexes PRC1 and PRC2 maintain embryonic stem cell (ESC) pluripotency by silencing lineage-specifying developmental regulator genes. Emerging evidence suggests that Polycomb complexes act through controlling spatial genome organization. We show that PRC1 functions as a master regulator of mouse ESC genome architecture by organizing genes in three-dimensional interaction networks. The strongest spatial network is composed of the four Hox gene clusters and early developmental transcription factor genes, the majority of which contact poised enhancers. Removal of Polycomb repression leads to disruption of promoter-promoter contacts in the Hox gene network. In contrast, promoter-enhancer contacts are maintained in the absence of Polycomb repression, with accompanying widespread acquisition of active chromatin signatures at network enhancers and pronounced transcriptional upregulation of network genes. Thus, PRC1 physically constrains developmental transcription factor genes and their enhancers in a silenced but poised spatial network. We propose that the selective release of genes from this spatial network underlies cell fate specification during early embryonic development.

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Nature genetics, , 1546-1718, , 2015

PMID: 26323060

Group Members

Latest Publications

Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression.

Kar G, Kim JK, Kolodziejczyk AA

Nature communications
8 2041-1723:36 (2017)

PMID: 28652613

Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.

Schoenfelder S, Sugar R, Dimond A

Nature genetics
1546-1718: (2015)

PMID: 26323060

The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements.

Schoenfelder S, Furlan-Magaril M, Mifsud B

Genome research
25 1549-5469:582-97 (2015)

PMID: 25752748

Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor.

GN Maertens, S El Messaoudi-Aubert, S Elderkin

The EMBO journal
29 15:2553-65 (2010)

DOI: 10.1038/emboj.2010.129

PMID: 20601937

Fission yeast Iec1-ino80-mediated nucleosome eviction regulates nucleotide and phosphate metabolism.

CJ Hogan, S Aligianni, M Durand-Dubief

Molecular and cellular biology
30 3:657-74 (2010)

DOI: 10.1128/MCB.01117-09

PMID: 19933844