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The dynamic interactome of Polycomb family complexes during stem cell differentiation

ABSTRACT: While the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics to study PcG proteins in mouse embryonic stem cells (mESCs) and neural progenitor cells (NPCs). We found the stoichiometry of PRC1 and PRC2 to be highly dynamic during neural differentiation.

OTHER RELATED OMICS DATASETS IN: PRJNA299693

INSTRUMENT(S): LTQ FT, LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Multipotent Stem Cell, Cell Culture, Embryonic Stem Cell

SUBMITTER: Susan Kloet

LAB HEAD: Michiel Vermeulen

PROVIDER: PXD003758 | Pride | 2016-05-19

REPOSITORIES: Pride

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			Action	DRS
	Asxl2_CONTROL_ESC_1.raw	Raw
	Asxl2_CONTROL_ESC_2.raw	Raw
	Asxl2_CONTROL_ESC_3.raw	Raw
	Asxl2_GFP_ESC_1.raw	Raw
	Asxl2_GFP_ESC_2.raw	Raw

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The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation.

Kloet Susan L SL Makowski Matthew M MM Baymaz H Irem HI van Voorthuijsen Lisa L Karemaker Ino D ID Santanach Alexandra A Jansen Pascal W T C PWTC Di Croce Luciano L Vermeulen Michiel M

Nature structural & molecular biology 20160613 7

Although the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics and genome-wide profiling to study PcG proteins in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We found that the stoichiometry and genome-wide binding of PRC1 and PRC2 were highly dynamic during neural differentiation. Intriguingly, we observed a dow ...[more]

PMID: 27294783

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Project description:The Nucleosome Remodeling and Deacetylase (NuRD) complex plays an important role in gene expression regulation, stem cell self-renewal, and lineage commitment. Yet little is known about the dynamics of NuRD during cellular differentiation. Here, we study these dynamics using genome-wide profiling and quantitative interaction proteomics in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). The genomic targets of NuRD are highly dynamic during differentiation, with most binding occurring at cell-type specific promoters and enhancers. We identify ZFP296 as a novel, ESC-specific NuRD interactor that also interacts with the SIN3A complex. ChIP-sequencing in Zfp296 knockout (KO) ESCs reveals decreased NuRD binding both genome-wide and at ZFP296 binding sites, although this has little effect on the transcriptome. Nevertheless, Zfp296 KO ESCs exhibit delayed induction of lineage-specific markers upon differentiation to embryoid bodies. In summary, we identify an ESC-specific NuRD interacting protein which regulates genome-wide NuRD binding and cellular differentiation.

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MTA proteins act redundantly within the NuRD complex to ensure fidelity of ES cell lineage commitment

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The HDAC inhibitor SAHA regulates CBX2 stability via a SUMO-triggered ubiquitin-mediated pathway in leukemia

Project description:Leukemias are characterized by bone marrow failure due to oncogenic mutations of hematopoietic stem cells (HSC) or blood precursor cells. HSC differentiation and self-renewal properties are tightly regulated by Polycomb group (PcG) proteins, a well-characterized family of transcriptional epigenetic regulators. PcG proteins form two canonical complexes: Polycomb repressive complex 1 (PRC1), and Polycomb repressive complex 2 (PRC2).CBX proteins link the activity of PRC1 with PRC2, serving as critical regulators of PcG-mediating activity. While the functional role of some CBX proteins in cancer has been largely explored, recent reports support the specific role of CBX2 in human tumors, thus it represent a promising new target for anti-cancer strategies. To date, chromodomain inhibitors have been identified for CBX7 , but no molecules inhibiting CBX2 have been described. Nevertheless, different chromatin-modulating drugs such as histone deacetylase inhibitors (HDACi) are reported to regulate CBX2 targets on chromatin, suggesting that HDACi might be used to indirectly modulate aberrant effects of CBX2 in cancer. We describe a novel SAHA-mediated mechanism of CBX2 post-translational regulation. We found that CBX2 undergoes SAHA-induced SUMO2/3 modification and that CBX2 SUMOylation promotes its ubiquitination and proteasome-dependent degradation. We also identified the specific molecular pathway and key players regulating CBX2 stability, demonstrating that CBX4 and RNF4 act as the E3 SUMO and E3 ubiquitin ligase, respectively. Additionally, CBX2-depleted leukemic cells display impaired proliferation, showing that CBX2 is required for leukemia cell clonogenicity. Our study provides the first evidence of a non-canonical SAHA-mediated anti-tumorigenic activity via CBX2 SUMOylation and degradation

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