Biology subjects

Margueron, R.

Publications and source records attributed to Margueron, R..

6 recordsLinked to original sources

bioRxiv2026

ULTRAPETALA1 remodels PRC2 recruitment to nucleosomes

Polycomb Repressive Complex 2 (PRC2) establishes transcriptional repression through trimethylation of histone H3 lysine 27 (H3K27me3), a modification essential for developmental patterning. Here, we describe a novel plant-specific PRC2 variant (PRC2.3) that employs a distinct nucleosome-targeting mechanism mediated by accessory factor ULTRAPETALA1 (ULT1), which promotes H3K27me3 deposition at over 1,300 developmental genes. The cryo-EM structure of the PRC2SWN-ULT1-nucleosome complex reveals that ULT1 antagonizes the canonical PRC2 binding mode and instead bridges PRC2 to the nucleosome using its own interaction surfaces. ULT1 binds consecutive purines in the nucleosomal DNA and the histone H2A/H2B acidic patch, while enabling PRC2 to accommodate H3K36 modifications. We further show that in planta ULT1 enhances H3K27me3 at purine-rich loci and at genes associated with H3K36 marks, and identify the ULT1-H2A/H2B interface as required for reproductive transition and flower organogenesis. Our findings demonstrate that PRC2 can deploy mechanistically distinct recruitment strategies to control key developmental switches.

Molecular Biology↗

bioRxiv2026

The FANCM-RMI1/2 complex promotes genomic instability and PARP inhibitor sensitivity in BRCA2-deficicient cells.

Cancer cells lacking BRCA1 or BRCA2 must adapt to survive and proliferate despite defective DNA repair and high genomic instability. Restoration of homologous recombination (HR) through loss of DNA end protection rescues growth defects and promotes PARP inhibitor (PARPi) resistance in BRCA1-deficient cells; however, the genetic basis of adaptation to BRCA2 loss remains largely unexplored. To delineate BRCA1- and BRCA2-specific adaptation trajectories, we established a fully isogenic screening platform in mouse embryonic stem cells engineered for acute depletion of either protein. This approach uncovered hundreds of genes with shared, distinct, or even opposing effects between the two BRCA-deficiency states. We identified FANCM and its interacting partners RMI1/2, CENPS/MHF1, CENPX/MHF2, and FAAP24 as essential in BRCA1-deficient cells but toxic in BRCA2-deficient contexts. Loss of FANCM in BRCA2-deficient cells alleviated genomic instability and proliferation defects by preventing RMI1/2-dependent replication fork degradation, without rescuing HR. Moreover, we show that the FANCM-RMI1/2 complex drives PARPi sensitivity in both mouse and human BRCA2-deficient cells, in contrast to the 53BP1-SHLD-CST axis in BRCA1-deficient cells. These findings reveal distinct adaptation routes to BRCA1 and BRCA2 loss and establish FANCM as a determinant of BRCA2-specific vulnerability and therapeutic response, with direct implications for tailoring prevention and therapy according to BRCA mutation status.

cancer biology↗

bioRxiv2024

The dual trxG/PcG protein ULTRAPETALA1 modulates H3K27me3 and directly enhances POLYCOMB REPRESSIVE COMPLEX 2 activity for fine-tuned reproductive transitions

AbstractThe antagonistic POLYCOMB (PcG) REPRESSIVE COMPLEX 2 (PRC2) and trithorax (trxG) chromatin machineries play a major role in orchestrating gene expression during the development of multicellular eukaryotes. These complexes are well known for depositing and maintaining the repressive H3K27me3 and activating H3K4me3 marks, respectively. However, the mechanisms that govern the switch between these functions remains elusive, especially in plants, whose lifelong, flexible development relies heavily on this process. Here we demonstrate that the plant specific ULTRAPETALA1 (ULT1) protein, previously reported as a trxG factor that antagonizes the PRC2 enzymatic subunit CURLY LEAF (CLF), also exhibits a repressive function, increasing H3K27me3 levels at over a thousand genes. We discovered a physical interaction between ULT1 and PRC2 components, particularly the SWINGER (SWN) enzymatic subunit. We further show that in vitro ULT1 significantly enhances the enzymatic activity of PRC2SWN, and to a lesser extent also that of PRC2CLF, corroborating our epigenomic and developmental genetic data that reveal different ULT1 activity depending on the catalytic subunit of the PRC2 complex. This study provides new insights into the relative activities of CLF and SWN and introduces a novel mechanistic framework for a chromatin switch mediated by a bivalent trxG/PcG factor. Key messageULTRAPETALA1 counteracts or promotes PRC2 activity at hundreds of developmental genes in Arabidopsis thaliana, and activates the deposition of the repressive H3K27me3 chromatin mark via direct interaction with PRC2. This is the first instance of a bivalent factor which functions as a cofactor of PRC2 HMTs.

genetics↗

bioRxiv2023

EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

Mutations in chromatin regulators or their histone substrates are widespread in cancer and often play decisive roles in tumorigenesis. These include Polycomb Repressive Complex 2 (PRC2), a histone H3 lysine 27 methyltransferase that shows distinct alterations in each of a range of tumor types. Mechanistically, this tumor-type specificity is poorly understood. Here, we model several of these alterations in a single isogenic system in order to reveal their comparative impacts on chromatin and transcription. Focusing then on gain-of-function substitutions in catalytic subunit EZH2, which occur in [~]25% of follicular lymphomas, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, and that these are alleviated by partial PRC2 inhibition. Ezh2Y641F also causes gains in existing H3K27 acetylation peaks and extensive gene expression changes. Remarkably, Ezh2Y641F transforms the transcriptomic response to PRC2 inhibition, leading notably to the induction of antigen presentation genes in mutant cells. Using a unique longitudinal cohort of FL patient samples we further strengthen the link between EZH2 mutation status and abnormal H3K27 methylation. This analysis also uncovered unexpected variability in the mutational landscape of successive biopsies from the same patient that points to the frequent co-existence of different clones. On a clinical level, this urges caution when stratifying patients based on single tumor sampling. Altogether, our results provide a mechanistic foundation for understanding how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

cancer biology↗

bioRxiv2019

GPIF constrains Polycomb Repressive Complex 2 activity in germ cells

The Polycomb machinery is required for the proper orchestration of gene expression by virtue of its critical role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a new cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This alteration of the epigenetic content of mature oocytes does not affect the initial number of follicles but is associated with a reduction of follicles in aging mice. We provide evidences that mature oocytes Ezhip -/- are not fully functional and that fertility is strongly impaired in Ezhip -/- females. Altogether, our study uncovers EZHIP as a novel functional player in the comprehensive chromatin remodeling that occurs in the gonads.

developmental biology↗

bioRxiv2018

The BAP1 deubiquitinase complex is a general transcriptional co-activator

In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAPl-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. We investigated the mechanism underlying BAP1.com-mediated transcriptional regulation and show that it functions neither in synergy nor by antagonism with the Polycomb machinery. Instead, our results provide compelling evidence that BAP1.com acts as a general transcriptional co-activator.

genomics↗