Biology subjects

Sauvageau, M.

Publications and source records attributed to Sauvageau, M..

4 recordsLinked to original sources

bioRxiv2026

LncRNA-mediated organization of oncogenic chromatin state is a targetable vulnerability in leukemia

Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of gene expression underlying various cellular functions, however, the functional and mechanistic contributions of most lncRNAs to tumorigenesis remain poorly defined, and targeting of lncRNAs is challenging with conventional therapeutic approaches. Here, we uncover human PAN3-AS1 and its murine ortholog Lnc35682, previously uncharacterized lncRNAs embedded within a conserved syntenic genomic locus, as highly expressed in acute myeloid leukemia (AML). Using genetic mouse models, human cell lines and primary patient samples, we show that PAN3-AS1 is essential for leukemia maintenance but dispensable for normal hematopoiesis. Mechanistically, we find that elevated PAN3-AS1 influences chromatin accessibility, thus promoting leukemia gene expression programs. This is mediated, at least in part, by PAN3-AS1s association with the nuclear lamina through a defined functional region that is required for its leukemogenic function. We further characterize a feed-forward regulatory circuit between PAN3-AS1 and its neighboring gene FLT3 that directly links the aberrant lncRNA functions to the FLT3-mutant AML subtype. To therapeutically exploit the regulatory node, we engineer a myeloid leukemia-preferentially targeted lipid nanoparticle (LNP) formulation and demonstrate effective delivery of siRNAs against endogenous targets into leukemia cells in experimental animals. LNP-siPAN3-AS1 alone or in combination with a clinically used FLT3 inhibitor, Gilteritinib, reduces leukemia burden and significantly delay leukemogenesis in vivo. Overall, our study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744058v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@10c9d42org.highwire.dtl.DTLVardef@12864e7org.highwire.dtl.DTLVardef@f87f6aorg.highwire.dtl.DTLVardef@750cbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

The lncRNA FENDRR fine-tunes FOXF1 protein levels through a negative feedback loop governing human embryonic lung fibroblast-to-myofibroblast transition

Precise control of transcription factor dosage is critical for lung mesenchymal development. The forkhead box transcription factor FOXF1 is a dosage-sensitive regulator of pulmonary vascularization and fibroblast differentiation, with haploinsufficiency causing the lethal neonatal disorder alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). A syntenically conserved long noncoding RNA (lncRNA), FENDRR, is divergently transcribed [~]1.7 kb upstream of FOXF1. Notably, ACDMPV-associated chromosomal deletions disrupting FENDRR or a distal enhancer regulating both FENDRR and FOXF1 have been identified. Consistent with a role in lung development, selective deletion of Fendrr in mice causes neonatal lethality with lung growth defects, as well as alveolar and vascular abnormalities. Here, we define the conserved expression patterns, isoform diversity, and subcellular localization of FENDRR and FOXF1 across human and murine embryonic lung cell types. Functional perturbation reveals a bidirectional regulatory circuit in which FOXF1 promotes FENDRR transcription, while FENDRR limits FOXF1 protein abundance without affecting mRNA levels. Transcriptomic analyses demonstrate overlapping target gene networks and opposing effects on fibroblast-to-myofibroblast differentiation. These findings uncover a rheostat-like regulatory layer by which the lncRNA FENDRR fine-tunes FOXF1 protein dosage to influence lung fibroblast cell fate response and offers additional context for the significance of FOXF1-FENDRR dysregulation in ACDMPV.

molecular biology↗

bioRxiv2024

ECSFinder: Optimized prediction of evolutionarily conserved RNA secondary structures from genome sequences

Accurate prediction of RNA secondary structures is essential for understanding the evolutionary conservation and functional roles of long noncoding RNAs (lncRNAs) across diverse species. In this study, we benchmarked two leading tools for predicting evolutionarily conserved RNA secondary structures (ECSs)--SISSIz and R-scape-- using two distinct experimental frameworks: one focusing on well-characterized mitochondrial RNA structures and the other on experimentally validated Rfam structures embedded within simulated genome alignments. While both tools performed comparably overall, each displayed subtle preferences in detecting ECSs. To address these limitations, we evaluated two interpretable machine learning approaches that integrate the strengths of both methods. By balancing thermodynamic stability features from RNALalifold and SISSIz with robust covariation metrics from R-scape, a random forest classifier significantly outperformed both conventional tools. This classifier was implemented in ECSfinder, a new tool that provides a robust, interpretable solution for genome-wide identification of conserved RNA structures, offering valuable insights into lncRNA function and evolutionary conservation. ECSfinder is designed for large-scale comparative genomics applications and promises to facilitate the discovery of novel functional RNA elements.

bioinformatics↗

bioRxiv2019

The Tug1 Locus is Essential for Male Fertility

BackgroundSeveral long noncoding RNAs (lncRNAs) have been shown to function as central components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, their functions remain largely uncharacterized. This is compounded by the fact that identifying lncRNA loci that have robust and reproducible phenotypes when mutated has been a challenge. ResultsWe previously generated a cohort of 20 lncRNA loci knockout mice. Here, we extend our initial study and provide a more detailed analysis of the highly conserved lncRNA locus, Taurine Upregulated Gene 1 (Tug1). We report that Tug1 knockout male mice are sterile with complete penetrance due to a low sperm count and abnormal sperm morphology. Having identified a lncRNA loci with a robust phenotype, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region (DNA, RNA, protein, or the act of transcription) have activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors three distinct regulatory activities - two noncoding and one coding: (i) a cis DNA repressor that regulates many neighboring genes, (ii) a lncRNA that can regulate genes by a trans-based function, and finally (iii) Tug1 encodes an evolutionary conserved peptide that when overexpressed impacts mitochondrial membrane potential. ConclusionsOur results reveal an essential role for the Tug1 locus in male fertility and uncover three distinct regulatory activities in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.

genomics↗