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Results for “Polycomb Repressive Complex 1”

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PubMed2025

Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation.

BCOR (BCL-6 corepressor) is a component of variant Polycomb Repressive Complex 1.1 (vPRC1.1), one of several vPRC1 complexes that catalyze histone H2A ubiquitination thought to play an important role in PRC2 binding and the deposition of H3K27me3 to silence genes. The PCGF Ub-like fold discriminator (PUFD) domain at the C-terminus of BCOR forms a heterodimer with PCGF1, serving as a critical interface for its polycomb-dependent functions. Internal tandem duplication (ITD) mutations in BCOR, causing in-frame duplications of 20 to 40 amino acids in the PUFD domain, are observed in heterogeneous tumors including sarcomas (kidney, bone, and endometrium) and neuroepithelial tumors in the brain. To dissect the molecular mechanisms underlying aberrant function of BCOR-ITD mutants, we employed mouse embryonic stem (mES) cells expressing either transgenic or endogenous BCOR-ITD. Our results indicate that the BCOR-ITD mutation does not disrupt the BCOR-PCGF1 interaction, instead maintaining the integrity of the vPRC1.1 complex. While displaying subtle changes in imprinted gene expression during differentiation toward a neural lineage, BCOR-ITD mutants also had no growth phenotype in culture. Furthermore, we found that CD24+ cells were enriched, as expected, during neural progenitor differentiation in both wildtype and mutant cells. However, sensitization of BCOR-ITD mES cells with EZH2 inhibitor during differentiation resulted in an unexpected enrichment of a CD24+CD26+ subpopulation, indicating aberrant cell fate that was also prevalent in a BCOR truncation mutant. Together, our results suggest that BCOR-ITD may largely retain wildtype function, but with increased susceptibility to synergistic stress on the Polycomb pathway.

Animals↗

PubMed1992

The polyhomeotic gene of Drosophila encodes a chromatin protein that shares polytene chromosome-binding sites with Polycomb.

The Polycomb group (PcG) genes in Drosophila melanogaster are required for maintenance of correct spatial expression of homeotic genes, and their products are thought to form either a regulatory network or act as a multimeric complex. Recently, it has been suggested that because of homology between Polycomb (Pc) and Su(var)205, PcG genes encode chromatin proteins required for the maintenance of a determined state in chromatin. The polyhomeotic (ph) gene is a member of the PcG of genes. We present DNA sequence of a ph cDNA, which encodes a 169-kD protein with a single putative zinc finger, a serine/threonine-rich region, and has glutamine repeats, suggesting that ph is a DNA-binding protein. Polyclonal antisera directed against ph protein bind to approximately 80 sites on polytene chromosomes. Most of these sites appear to be the same as those recognized by antibodies to Pc protein. ph protein binds to insertion sites of constructs containing DNA from the bithoraxoid (bxd) region of the Bithorax complex, showing that ph binding to chromatin is DNA dependent. The same bxd constructs are recognized by Pc protein, strongly supporting the hypothesis that ph and Pc interact directly.

Amino Acid Sequence↗

PubMed1992

Analysis of the functional role of the Polycomb chromo domain in Drosophila melanogaster.

The chromo domain was identified as a homologous protein motif between Polycomb (Pc)--a member of the Pc-group genes encoding transcriptional repressors of the homeotic genes--and HP1--a heterochromatin-associated protein encoded by the suppressor of position effect variegation gene Su(var)205. Together with previous genetic studies, this molecular similarity supports the suggestion of a common mechanism used for generating heterochromatin and for repressing homeotic genes. The evolutionary conservation of the chromo domain throughout the animal and plant kingdoms implies an important functional role for this protein motif. We have used transgenic lines as well as transient expression assays employing Drosophila tissue culture cells to study the functional role of the Pc chromo domain. Wild-type Pc protein is endogenously expressed in SL2 cells and is found in large immunologically visible complexes. Mutated Pc proteins were expressed as Pc-beta-galactosidase fusion proteins, and their nuclear distribution was examined by indirect immunofluorescence in tissue culture cells and on polytene chromosomes of transgenic larvae. We show that carboxy-terminal truncations of the Pc protein do not affect chromosomal binding of the fusion protein. However, mutations affecting only the chromo domain including in vitro generated deletions, as well as point mutations, abolish chromosomal binding. Our results demonstrate for the first time that the chromo domain is important for the function of Pc and that it is absolutely required for binding of Pc protein to chromatin. Some of the nuclear patterns generated by the mutated forms of the fusion proteins suggest, furthermore, that the chromo domain could be involved in a packaging mechanism, essential for compacting chromosomal proteins within heterochromatin or heterochromatin-like complexes.

Alleles↗

PubMed2026

Mechanisms of Transcriptional Regulation by Salicylic Acid Receptors.

Salicylic acid (SA) is a key phytohormone that activates plant defense responses 1-3. In Arabidopsis, NPR1 (also known as NIM1) and NPR3/NPR4 have been identified as dual SA receptors responsible for perceiving SA 4-6. However, the mechanisms of how SA binding to the NPR proteins leads to induction of defense gene expression remain unclear. Here, we elucidate how SA triggers transcriptional activation via NPR1 and relieves transcriptional repression mediated by NPR3/NPR4. We identified Mediator Complex Subunit 15A (MED15A) as a bridge between NPR1 and the Mediator complex governing transcription. SA induces direct interaction of NPR1 with MED15A. Structural and functional analysis showed that the binding of NPR1 to MED15A is essential for NPR1-mediated transcriptional activation. Meanwhile, SA relieves transcriptional repression mediated by NPR3/NPR4. NIM1-interacting 1 (NIMIN1) interacts with NPR3/NPR4 and the Topless (TPL) co-repressor, connecting them to Polycomb Repressive Complex 2 (PRC2) to mediate H3K27 trimethylation of SA-responsive genes. SA inhibits the interactions between NPR3/NPR4 and NIMIN1, reduces H3K27 trimethylation levels and increases histone acetylation of the target genes to release NPR3/NPR4-mediated repression. Our study offers a comprehensive view of SA-mediated defense gene activation. These findings lay a foundation for designing more effective SA analogs as agrochemicals and for engineering crop resistance by manipulating SA perception and signaling.

Journal Article↗

PubMed2025

Mapping early PRC2 nucleation sites upon Suz12 reintroduction reveals features of de novo Polycomb recruitment.

Polycomb domains safeguard cell identity by maintaining lineage-specific chromatin states enriched in repressive histone modifications, preserving the epigenetic memory of cell lineages. While Polycomb Repressive Complex 2 (PRC2) can re-establish its occupancy after perturbation, the mechanisms that guide de novo Polycomb recruitment remain unclear. To address this, we engineered an auxin-inducible degradation system to reversibly deplete and reintroduce the endogenous PRC2 core subunit Suz12 in mouse embryonic stem cells (mESCs). Genome-wide profiling at an early recovery time point revealed ~1,100 PRC2 nucleation sites, characterized by rapid Suz12 and histone H3K27me3 re-accumulation with strong signal, with minimal impact on gene expression. These sites were significantly enriched at bivalent promoters, coinciding with unmethylated CpG islands and chromatin states associated with developmental regulation, and were largely conserved in differentiated cells. Motif analysis identified G/C-rich DNA sequences associated with E2F and zinc-finger proteins, alongside strong co-occupancy with MTF2 and JARID2, two PRC2 cofactors previously implicated in Polycomb targeting. Notably, a subset of nucleation sites overlapped with long-range chromatin interaction anchors in histone H3K27me3 HiChIP datasets. These findings reveal that PRC2 de novo nucleation sites are associated with a combination of chromatin states, DNA sequence features, cofactor co-occupancy and spatial genome organization, suggesting that epigenetic memory can be re-established through defined genomic and chromatin features.

Epigenetic memory↗

PubMed2025

Multiple Epigenetic Mechanisms Functionally Cooperate to Silence Expression of Somatostatin Receptor Type 2 in Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNETs) are a rare and understudied set of cancers, with increasing incidence. Neuroendocrine tumors are unique in the fact that they express high levels of the somatostatin receptor type 2 (SSTR2), which represents a target for both tumor imaging and therapeutics. PNET grade inversely correlates with SSTR2 tumor staining and higher tumor grade is associated with poor patient prognosis. With no known mutations, SSTR2 expression is believed to be lost through aberrant epigenetic mechanisms. Enhanced knowledge of the epigenetic biology and players controlling SSTR2 expression may allow for identification of novel PNET imaging and treatment modalities. Through in-depth studies, we found that the specific de novo DNA methyltransferase (DNMT), DNMT3B, is responsible for SSTR2 gene CpG methylation and silencing. Using DNMT3B as a starting point, along with the concept of functional crosstalk between various epigenetic mechanisms, we further discovered that Polycomb Repressor Complexes 1 and 2 (PRC1 and PRC2) play important roles in silencing SSTR2. Moreover, we found several histone lysine demethylases, enzymes that remove activating histone H3K4 methylation marks, to be critical for silencing expression of SSTR2. We additionally identified several chromatin remodeling enzymes/complexes as cellular factors that negatively regulate SSTR2 expression. Finally, using the HiBiT luminescent reporter system, we exploited functional chemo-genomic screens to further expand our knowledge of SSTR2 epigenetic control. These screens both reinforced several of our initial findings and helped to identify additional silencing mechanism potentially regulating SSTR2 expression. A commonality in our findings point to the presence, or necessity, of Class I HDACs in nearly all the epigenetic silencing mechanisms characterized. Overall, our work demonstrates that SSTR2 gene expression is likely silenced through various dynamic and interconnected epigenetic events, resulting in a compacted, transcriptionally repressed chromatin environment. Our study offers novel potential therapeutic targets and combinations to best increase expression of SSTR2, which are currently being tested in pre-clinical studies from our group, with the goal of future clinical trials aimed at increasing SSTR2 expression in high-grade, SSTR2-low NET patients.

Journal Article↗

PubMed2026

Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. METHODS: Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. RESULTS: Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. CONCLUSIONS: Dual EZH2 and MEK inhibitors yield additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.

EZH2 inhibitor↗