Biology subjects

Besson, A.

Publications and source records attributed to Besson, A..

7 recordsLinked to original sources

bioRxiv2026

u4atac regulates cilium biogenesis through splicing of the minor intron of tmem107l and rfx7b in zebrafish developing brain

Bi-allelic variants of RNU4ATAC, transcribed into the minor spliceosome component U4atac snRNA, are associated to variable severity of microcephaly, growth retardation, skeletal dysplasia and immunodeficiency as main features. Previous studies highlighted the dramatic effect of U4atac deficiency on splicing of U12-type introns, which represent less than 1% of all introns in the human genome. More recently, our team evidenced a link between U4atac and the primary cilium/centrosome complex through the identification of patients carrying RNU4ATAC bi-allelic variants and exhibiting an atypical Joubert syndrome, a well-known ciliopathy. Yet, the underlying mechanisms remain elusive. Here, we further explored the link of RNU4ATAC to primary cilium and aimed at identifying ciliary U12-type intron containing genes that contribute to the brain abnormalities seen in patients. For that, we performed a transcriptomic analysis of heads of our morpholino oligonucleotide (MO)-mediated u4atac zebrafish model. Through the combined analysis of the generated dataset with those obtained from RNU4ATAC patient cells, we identified two candidate genes: TMEM107, coding for a structural protein of the cilium transition zone, and RFX7, encoding a transcription factor involved in primary cilium formation. By conducting complementary genetic approaches in zebrafish model, we showed that both gene orthologues, tmem107l and rfx7b, functionally interact with u4atac and are required for correct brain development. Altogether, our findings establish TMEM107 and RFX7 as key components of the molecular pathway linking U4atac dysfunction to ciliary defects and impaired brain development, providing new physiopathological insights and therapeutic perspectives for RNU4ATAC-related disorders.

genetics↗

bioRxiv2026

Loss of p27Kip1 causes metabolic reprogramming and is sufficient to induce a Warburg effect and glutamine addiction in untransformed cells

The metabolic needs of a cell are tightly linked to its proliferative state and increasing evidence indicate an extensive bidirectional crosstalk between metabolic pathways and cell cycle regulators. In cancer cells, metabolism is reprogrammed to couple energetic needs and relentless proliferation. The cyclin/CDK inhibitor p27Kip1 (p27) is frequently inactivated in cancers. p27 is also involved in multiple cellular processes, including transcriptional regulation or autophagy induction. Herein, we investigated the effect of p27 loss on cell metabolism. The knockout of p27 in immortalized mouse fibroblasts increases glucose uptake and glycolysis, while decreasing mitochondrial ATP production, consistent with induction of a Warburg effect, and this was accompanied by an increased glutamine dependency to feed the TCA cycle. Our data suggest that p27 loss causes this phenotype through extensive transcriptional remodeling of metabolic gene expression. Importantly, p27 silencing in human retinal RPE1-hTERT cells was sufficient to induce a Warburg effect. Together, these results reveal a new function of p27 in regulating energy metabolism and that loss of p27 expression is sufficient to induce metabolic reprogramming and a Warburg effect, suggesting that p27 inactivation in cancer cells not only results in the loss of cell cycle inhibition but also enables the metabolic rewiring needed for increased proliferation.

cell biology↗

bioRxiv2025

Facilitating genome annotation using ANNEXA and long-read RNA sequencing

With the advent of complete genome assemblies, genome annotation has become essential for the functional interpretation of genomic data. Long-read RNA sequencing (LR-RNAseq) technologies have significantly improved transcriptome annotation by enabling full-length transcript reconstruction for both coding and non-coding RNAs. However, challenges such as transcript fragmentation and incomplete isoform representation persist, highlighting the need for robust quality control (QC) strategies. This study presents ANNEXA, a pipeline designed to enhance genome annotation using LR-RNAseq data while also providing QC for reconstructed genes and transcripts. ANNEXA integrates two transcriptome reconstruction tools, StringTie2 and Bambu, applying stringent filtering criteria to improve annotation accuracy. It also incorporates deep learning models to evaluate transcription start sites (TSSs) and employs the tool FEELnc for the systematic annotation of long non-coding RNAs (lncRNAs). Additionally, the pipeline offers intuitive visualisations for comparative analyses of coding and non-coding repertoires. Benchmarking against multiple reference annotations revealed distinct patterns of sensitivity and precision for both known and novel genes and transcripts and mRNAs and lncRNAs. To demonstrate its utility, ANNEXA was applied in a comparative oncology study involving LR-RNAseq of two human and eight canine cancer cell lines. The pipeline successfully identified novel genes and transcripts across species, expanding the catalog of protein-coding and lncRNA annotations in both species. Implemented in Nextflow for scalability and reproducibility, ANNEXA is available as an open-source tool: https://github.com/IGDRion/ANNEXA.

bioinformatics↗

bioRxiv2023

Single-cell transcriptome landscape of developing fetal gonads defines somatic cell lineage specification in humans

Gonad development is an exciting model to study cell fate commitment. However, the specification and differentiation of somatic cell lineages within the testis and the ovary are incompletely characterized, especially in humans. In fact, a better understanding of sex determination first requires the identification of all the cell types involved and of their dynamic expression programs. Here we present a comprehensive analysis of approximately 128,000 single cells collected from 33 fetal testes and ovaries between 5 and 12 postconceptional weeks. In particular, a focused analysis of somatic cells allowed us to identify a common population of bipotential progenitors derived from the coelomic epithelium of both male and female gonads and capable of committing to either a steroidogenic or a supporting fate. Moreover, we have shown that early supporting cells, prior to further differentiation into Sertoli or granulosa cells, also give rise to the rete testis/ovarii lineage. Finally, we found that the ovary retains the capacity to feed the supporting cell pool for an extended period of time, directly from the surface epithelial cells and, bypassing the bipotential progenitor step. Altogether, our results provide an unprecedented revisiting of the human gonadal sex determination process.

developmental biology↗

bioRxiv2022

p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation

p57Kip2 is a cyclin/CDK inhibitor and a negative regulator of cell proliferation. Remarkably, p57 is the only CDK inhibitor required for embryonic development and p57 knockout mice display multiple developmental anomalies, including intestinal shortening. Here, we report that p57 regulates intestinal stem cell (ISC) fate and proliferation in a CDK-independent manner during intestinal development. In absence of p57, proliferation in intestinal crypts is markedly increased and genetic labelling experiments revealed an amplification of transit amplifying cells and of Hopx+ ISCs, which are no longer quiescent. On the other hand, Lgr5+ crypt-base columnar (CBC) cells were unaffected. RNA-Seq analyses of Hopx+ ISCs show major changes in gene expression in absence of p57. We found that p57 binds to and inhibits the activity of Ascl2, a transcription factor critical for ISC specification and maintenance, by participating in the recruitment of a corepressor complex to Ascl2 target gene promoters. Thus, our data suggests that during intestinal development, p57 plays a key role in maintaining Hopx+ stem cell quiescence and repressing the ISC phenotype outside of the crypt bottom by inhibiting the transcription factor Ascl2 in a CDK-independent manner.

cell biology↗

bioRxiv2020

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

Autophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies have shown that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy. However, the underlying mechanism remains unknown. Here, we report that in amino acid deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During prolonged amino acid starvation, a fraction of p27 is recruited to lysosomes where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 lysosomal localization and activation. p27 binding to LAMTOR1 prevents Ragulator assembly and function and subsequent mTORC1 activation, thereby promoting autophagy. Conversely, upon amino acid withdrawal, p27-/- cells exhibit elevated mTORC1 signaling, impaired lysosomal activity and autophagy, and resistance to apoptosis. This is associated with sequestration of TFEB in the cytoplasm, preventing the induction of lysosomal genes required for lysosomal function. Silencing of LAMTOR1 or mTOR inhibition restores autophagy and induces apoptosis in p27-/- cells. Together, these results reveal a direct, coordinated regulation between the cell cycle and cell growth machineries.

cell biology↗

bioRxiv2019

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia which expresses the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation.

cancer biology↗