Biology subjects

Thibault-Carpentier, C.

Publications and source records attributed to Thibault-Carpentier, C..

4 recordsLinked to original sources

bioRxiv2026

Comparison of cell-cycle gene expression dynamics and mRNA kinetics across mouse and human pluripotent systems

Cell-cycle remodeling is fundamental to pluripotency and lineage commitment, yet whether its transcriptional and post-transcriptional architecture is conserved across species and developmental states has remained unresolved. Here we introduce Ciclopes, a biology-informed deep-learning framework that resolves continuous cell-cycle phase and phase-dependent mRNA transcription and degradation directly from single-cell RNA sequencing. Applying Ciclopes across six mouse and human pluripotent stem-cell systems spanning naive and primed states, we uncover striking divergence in transcriptional complexity and oscillatory control: mouse systems sustain elevated baseline expression of core cell-cycle regulators, while human systems trade higher baseline expression for larger oscillatory amplitude. Strikingly, mRNA degradation timing remain far more conserved across systems than transcription timing, exposing post-transcriptional regulation as a stable evolutionary backbone. As human iPSCs differentiate into definitive endoderm, cells progressively exit the cell cycle, cell-cycle-coupled gene networks contract, and surviving regulators oscillate with larger amplitude. Ciclopes establishes a general framework for dissecting how pluripotent cells tune proliferation across evolutionary and developmental transitions.

systems biology↗

bioRxiv2024

TFE3 fusion proteins drive oxidative metabolism, ferroptosis resistance and general RNA synthesis in translocation renal cell carcinoma

The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterised. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos) increasing functional OxPhos levels. Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumour aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance and more generally stimulates RNA synthesis. SynopsisDefining the gene expression programs regulated by TFE3 fusion proteins in translocation renal cell carcinoma. TFE3 fusion proteins promote expression of oxidative metabolism genes and oxidative metabolism in tRCC. TFE3 fusion proteins regulate glutathione metabolism and ferroptosis resistance in tRCC. TFE3 fusion proteins bind broadly at active promoters and stimulate RNA synthesis in tRCC. Epithelial-to-mesenchymal transition in tRCC is accompanied by enrichment in myofibroblastic cancer-associated-fibroblasts and poor patient outcome. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/620047v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b9dcb6org.highwire.dtl.DTLVardef@495f42org.highwire.dtl.DTLVardef@10d1770org.highwire.dtl.DTLVardef@7df40c_HPS_FORMAT_FIGEXP M_FIG C_FIG The paper explained. Problem.Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer characterised by genetic translocation events frequently involving transcription factor TFE3 or more rarely TFEB. While the resulting fusion proteins are considered as the oncogenic drivers, their mechanism of action remains poorly understood. Results.By integrative multi-omics analyses in tRCC cell lines and patient tumors together with loss and gain of function experiments, we found broad binding of TFE3-fusion proteins at active promoters and identified a core set of target genes involved in multiple pathways, including oxidative metabolism (OxPhos) and ferroptosis. Consequently, tRCC cell lines displayed higher functional OxPhos levels and patient tumours displayed elevated OxPhos scores and ferroptosis resistance gene expression. Analyses of tRCC patient transcriptome data further revealed that mesenchymal tRCC tumours are enriched in myofibroblastic cancer associated fibroblasts that are hallmarks of poor prognostic outcome. ImpactThis study advances understanding of the molecular mechanisms underlying oncogenic transformation by TFE3 fusion proteins by defining a core program of gene expression and key features of tumour cells and their microenvironment that negatively impact patient outcome. Our integrative multi-omics and functional analyses reveal how extensive genomic binding of TFE3 fusion proteins drives high levels of oxidative metabolism, ferroptosis resistance and general RNA synthesis.

cancer biology↗

bioRxiv2019

Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production

ObjectiveEnteroendocrine cells (EECs) of the gastro-intestinal tract sense gut luminal factors and release peptide hormones or serotonin (5-HT) to coordinate energy uptake and storage. Our goal is to decipher the gene regulatory networks controlling EECs specification from enteroendocrine progenitors. In this context, we studied the role of the transcription factor Rfx6 which had been identified as the cause of Mitchell-Riley syndrome characterized by neonatal diabetes and congenital malabsorptive diarrhea. We previously reported that Rfx6 was essential for pancreatic beta cell development and function, however, the role of Rfx6 in EECs differentiation remained to be elucidated.\n\nMethodsWe examined the molecular, cellular and metabolic consequences of constitutive and conditional deletion of Rfx6 in the embryonic and adult mouse intestine. We performed single cell and bulk RNA-Seq to characterize EECs diversity and identify Rfx6-regulated genes.\n\nResultsRfx6 is expressed in the gut endoderm; later it is turned on in, and restricted to, enteroendocrine progenitors and persists in hormone-positive EECs. In the embryonic intestine, the constitutive lack of Rfx6 leads to gastric heterotopia, suggesting a role in the maintenance of intestinal identity. In the absence of intestinal Rfx6, EECs differentiation is severely impaired both in the embryo and adult. However, the number of serotonin-producing enterochromaffin cells and mucosal 5-HT content are increased. Concomitantly, Neurog3-positive enteroendocrine progenitors accumulate. Combined analysis of single-cell and bulk RNA-Seq data revealed that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin (EC) cells and the Peptidergic Enteroendocrine (PE) cells, whose differentiation programs are differentially regulated by Rfx6. Rfx6 operates upstream of Arx, Pax6 and Isl1 to trigger the differentiation of peptidergic EECs such as GIP-, GLP-1- or CCK-secreting cells. On the contrary, Rfx6 represses Lmx1a and Tph1, two genes essential for serotonin biosynthesis. Finally, we identified transcriptional changes uncovering adaptive responses to the prolonged lack of enteroendocrine hormones and leading to malabsorption and lower food efficiency ratio in Rfx6-deficient mouse intestine.\n\nConclusionThese studies identify Rfx6 as an essential transcriptional regulator of EECs specification and shed light on the molecular mechanisms of intestinal failures in human RFX6-deficiencies such as Mitchell-Riley syndrome.

developmental biology↗

bioRxiv2018

BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments

Genetic factors are known to contribute to Late Onset Alzheimers disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimers disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a [~]195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.

neuroscience↗