Imperial College London

ProfessorMatthiasMerkenschlager

Faculty of MedicineInstitute of Clinical Sciences

Professor of Cell Biology
 
 
 
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Contact

 

+44 (0)20 3313 8239matthias.merkenschlager

 
 
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Location

 

4005CRB (Clinical Research Building)Hammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

2 results found

Landeira D, Bagci H, Malinowski AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG, Landeira D, Bagci H, Malinowski AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG, Landeira D, Bagci H, Malinowski AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG, Landeira D, Bagci H, Malinowski AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG, Landeira D, Bagci H, Malinowski AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AGet al., 2015, Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development, CELL REPORTS, Vol: 12, Pages: 573-586, ISSN: 2211-1247

Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2(-/-) ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2(-/-) with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development.

JOURNAL ARTICLE

Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ, Merkenschlager M, Fisher AG, Azuara V, Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ, Merkenschlager M, Fisher AG, Azuara V, Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ, Merkenschlager M, Fisher AG, Azuara Vet al., 2004, A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction, CELL CYCLE, Vol: 3, Pages: 1645-1650, ISSN: 1538-4101

Mammalian embryonic stem (ES) cells can either self-renew or generate progenitor cells that have a more restricted developmental potential. This provides an important model system to ask how pluripotency, cell commitment and differentiation are regulated at the level of chromatin-based changes that distinguish stem cells from their differentiated progeny. Here we show that the differentiation of ES cells to neural progenitors results in dynamic changes in the epigenetic status of multiple genes that encode transcription factors critical for early embryonic development or lineage specification. In particular, we demonstrate that DNA replication at a subset of neural-associated genes including Pax3, Pax6, Irx3, Nkx2.9 and Mash1 is advanced upon neural induction, consistent with increased locus accessibility. Conversely, many ES-associated genes including Oct4, Nanog, Utf1, Foxd3, Cripto and Rex1 that replicate early in ES cells switch their replication timing to later in S-phase in response to differentiation. Detailed analysis of the Rex1 locus reveals that delayed replication extends to a 2.8 Mb region surrounding the gene and is associated with substantial reductions in the level of histone H3K9 and H4 acetylation at the promoter. These results show that loss of pluripotency (and lineage choice) is associated with extensive and predictable changes in the replication timing of key regulator genes.

JOURNAL ARTICLE

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