Biology subjects

Gregoire, E.

Publications and source records attributed to Gregoire, E..

3 recordsLinked to original sources

bioRxiv2026

Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma

Low-grade endometrial stromal sarcoma (LGESS) exhibits frequent chromosomal translocations that fuse various subunits of the NuA4/TIP60 co-activator complex to subunits of the Polycomb Repressive Complex 2 (PRC2) complex. LGESS fusion proteins, such as the commonly occurring JAZF1-SUZ12, have been shown to upregulate genes through mislocalization of NuA4/TIP60 activity to Polycomb target genes. In this study, we characterized an interesting recurrent fusion protein in LGESS that fused a NuA4/TIP60 component, MBTD1, to EZHIP. EZHIP is a recently described vertebrate protein that enzymatically inhibits methyltransferase activity of the PRC2 complex and is a potent oncogene. The MBTD1-EZHIP fusion protein forms a chimeric TIP60-PRC2.1 complex and drastically reduces H3K27me3 levels at Polycomb target genes, similar to EZHIP-overexpressing cancers. However, unlike EZHIP overexpression, MBTD1-EZHIP requires mislocalization of NuA4/TIP60 activity through the MBTD1 protein to upregulate oncogenes. Despite differences in the finer molecular mechanisms, MBTD1-EZHIP and the common JAZF1-SUZ12 fusion protein upregulated similar sets of genes in cell lines, showing a convergence of oncogenic gene expression. Surprisingly, unlike in cellular models, JAZF1-SUZ12 translocated patient samples showed not only upregulation of genes driven by increased H4K8ac and decreased H3K27me3 but also downregulation of specific genes due to accumulated H3K27me3, revealing an additional oncogenic mechanism in LGESS.

cancer biology↗

bioRxiv2023

Ensembling Unets, sparse representation and low dimensional visualization for rare chromosomal aberration detection in light microscopy images

AO_SCPLOWBSTRACTC_SCPLOWIn biological dosimetry, a radiation dose is estimated using the average number of chromosomal aberration per peripheral blood lymphocytes. To achieve an adequate precision in the estimation of this average, hundreds of cells must be analyzed in 2D microscopy images. Currently, this analysis is performed manually, as conventional computer vision techniques struggle with the wide variety of shapes showcased by chromosomes. The false discovery rate of current automated detection systems is high and variable, depending on small variations in data quality (chromosome spread, illumination variations ...), which makes using it in a fully automated fashion impossible. Automating chromosomal aberration is needed to reduce diagnosis time. Furthermore, an automated system can process more images, which improves confidence intervals around the estimated radiation dose. We build an object detection model to automate chromosomal aberration detection using recent advances in deep convolutional neural networks and statistical learning. We formulated the problem of rare aberration detection as a heatmap regression problem requiring the minimization of a sparsity-promoting loss to reduce the false alarm rate. Our Unet-based approach is analoguous to a one-stage object detector, and keeps the number of hyperparameters to a minimum. Finally, we demonstrate large performance improvements using an ensemble of checkpoints collected during a single run of training. A PCA-based strategy is used to provide cues for interpretation of our deep neural network-based model. The methodology is demonstrated on real, large, and challenging datasets depicting rare chromosomal aberrations and is favorably compared to a reference dosimetry technique.

bioinformatics↗

bioRxiv2019

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

During kidney development, WNT/{beta}-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of renal stem cells. Here we show that the two signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/{beta}-catenin signalling and their genetic deletion leads to a rapid decline of renal progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr-dependent and independent functions for these ligands during kidney formation.

developmental biology↗