Biology subjects

Dossin, F.

Publications and source records attributed to Dossin, F..

4 recordsLinked to original sources

bioRxiv2026

Tethering-mediated recruitment of pioneer factors by NuRD enables signal dependent gene activation and protects cell identity

Cell identity relies on precise control of transcription factor (TF) activity, localization and interpretation of signaling. Mitogen-activated protein kinase (MAPK) signaling regulates transcription via the ERK kinase, phosphorylating components of the Mediator complex to regulate its association with TF-bound enhancers. Here we describe two distinct forms of TF association related to signaling response, stable DNA recognition and tethering to active sites of transcription. We find that the tethering of TFs at these active sites is both essential for signaling response and cell identity. To identify tethering substrates, we focused on signaling dependent associations with the transcriptional coregulator, the Mediator, and find the NuRD complex is engaged with the Mediator at active promoters and enhancers. Here, NuRD functions as a molecular scaffold recruiting pioneer TFs like SOX2 independently of DNA sequence, enhancing ERK dependent transcription while sequestering these factors away from context inappropriate binding sites elsewhere in the genome. Balancing the recognition of a restricted spectrum of canonical DNA sites by pioneer factors while retaining them at high concentrations in the vicinity of transcription supports robust transcriptional response, ensures plasticity in differentiation and explains why these factors bind a fraction of their naturally occurring sites in any given cell type.

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↗

bioRxiv2020

SPEN is Required for Xist Upregulation during Initiation of X Chromosome Inactivation

At initiation of X chromosome inactivation (XCI), Xist is monoallelically upregulated from the future inactive X (Xi) chromosome, overcoming repression by its antisense transcript Tsix. Xist recruits various chromatin remodelers, amongst them SPEN, which are involved in silencing of X-linked genes in cis and establishment of the Xi. Here, we show that SPEN plays an important role in the initiation of XCI. Spen null female mouse embryonic stem cells (ESCs) are defective in Xist upregulation upon differentiation. We find that Xist-mediated SPEN recruitment to the Xi chromosome happens very early in XCI, and that SPEN-mediated silencing of the Tsix promoter is required for Xist upregulation. Accordingly, failed Xist upregulation in Spen-/- ESCs can be rescued by concomitant removal of Tsix. These findings indicate that SPEN is not only required for the establishment of the Xi, but is also crucial in the initiation of the XCI process.

developmental biology↗

bioRxiv2020

m6A RNA methylation regulates the fate of endogenous retroviruses

Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that impact genome regulation and cell physiology throughout their RNA-centered life cycle1. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases2-4. Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m6A RNA methylation as a novel means of ERV restriction. Methylation of ERV mRNAs is catalyzed by the complex of methyltransferase-like METTL3/METTL145 proteins whose depletion, along with their accessory subunits, WTAP and ZC3H13, led to increased mRNA abundance of Intracisternal A-particles (IAPs) and related ERVK elements specifically, by targeting their 5UTR region. Using controlled auxin-dependent degradation of the METTL3/METTL14 enzymatic complex, we showed that IAP mRNA and protein abundance is dynamically and inversely correlated with m6A catalysis. By monitoring mRNA degradation rates upon METTL3/14 double degron, we further proved that m6A methylation destabilizes IAP transcripts. Finally, similarly to m6A writers, triple knockout of the m6A readers YTHDF1, DF2 and DF36 increased IAP mRNA abundance. This study sheds light onto a novel function of RNA methylation in protecting cellular integrity by clearing reactive ERV-derived RNA species, which may be especially important when transcriptional silencing is less stringent.

cell biology↗