Biology subjects

Orgeur, M.

Publications and source records attributed to Orgeur, M..

6 recordsLinked to original sources

bioRxiv2025

Evaluation of the role of whiB6 and kdpDE in the dominant multidrug resistant clone Mycobacterium tuberculosis B0/W148

Multidrug resistant (MDR) strains of Mycobacterium tuberculosis represent an obstacle to eradicating tuberculosis (TB) due to the low treatment success rate of MDR TB. Among them, the MDR B0/W148 clone has recently evolved from the M. tuberculosis Beijing lineage 2 and widely disseminated in Russia and Europe. To get more insights into the genetic factors underlying the evolutionary success of the MDR M. tuberculosis B0/W148 clone in addition to environmental and patient-related features, we focused on two mutations specific from this clone that are found in the transcriptional regulators WhiB6 and KdpDE and investigated in a H37Rv strain background the transcriptional profile associated with these mutations and their impact on the in vitro and in vivo growth characteristics. Through the construction and use of H37Rv{Delta}whiB6, H37Rv{Delta}kdpDE, and complemented strains, we found that both mutations did not impair the in vitro growth of M. tuberculosis in standard mycobacterial growth media. The mutation T51P in whiB6 prevented the upregulation of 9 genes in the esx-1 core region and 44 genes elsewhere in the genome, while the deletion of two nucleotides in kdpD leads to a fusion protein of KdpD with KdpE that inhibits the transcriptional activity of KdpE. Both mutations did not lead to hypervirulence in a mouse infection model. These results point to the role of other MDR B0/W148 specific mutations in the wide geographic diffusion of this clone, and/or put in question a hypothesized hypervirulence as driving factor for this large dissemination. ImportanceHuman tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, remains a global public health issue estimated to have been responsible for 1.25 million deaths in 2023. Multidrug resistant (MDR) strains of M. tuberculosis, resistant to rifampicin and isoniazid, lead to lower treatment success. Among them, the MDR B0/W148 clone has widely disseminated in Russia and Europe. To get more insights into the genetic factors underlying the evolutionary success of this clone, we investigated two strain-specific mutations found in the transcriptional regulators WhiB6 and KdpDE. By constructing and analysing laboratory M. tuberculosis strains carrying these specific mutations, we found numerous changes in their transcriptional profiles, whereas we observed only little impact of these mutations on virulence of M. tuberculosis in a mouse infection model. Our study provides new insights into the transcriptional landscape of the selected MDR strains, although no direct connection to virulence could be established.

microbiology↗

bioRxiv2023

Mesenchymal Osr1+ cells regulate embryonic lymphatic vessel formation

The lymphatic system is formed during embryonic development by the commitment of specialized lymphatic endothelial cells (LECs) and their subsequent assembly in primary lymphatic vessels. While lymphatic cells are in continuous contact with mesenchymal cells during development and in adult tissues, the role of mesenchymal cells in lymphatic vasculature development remains poorly characterized. Here, we show that a subpopulation of mesenchymal cells expressing the transcription factor Osr1 are in close association with migrating LECs and established lymphatic vessels in mice. Lineage tracing experiments revealed that Osr1+ cells precede LEC arrival during lymphatic vasculature assembly in the back of the embryo. Using Osr1-deficient embryos and functional in vitro assays, we show that Osr1 acts in a non-cell autonomous manner controlling proliferation and early migration of LECs to peripheral tissues. Thereby, mesenchymal Osr1+ cells control in a bimodal manner the production of extracellular matrix scaffold components and signal ligands critical for lymphatic vessels formation.

developmental biology↗

bioRxiv2018

In addition to being a marker for muscle connective tissue, Odd skipped-related 2 (OSR2) is expressed in differentiated muscle cells during chick development

The zinc finger transcription factor, Odd skipped-related 2 (OSR2) is a recognized marker of connective tissue in chick embryos. OSR2 gain- and loss-of-function experiments indicate a role in irregular connective tissue differentiation in chick limb undifferentiated cells. Re-investigation of OSR2 transcript location during chick development with in situ hybridization experiments showed that OSR2 was also expressed in differentiated muscle cells in limbs and head. OSR2 expression was also observed in differentiated myotubes in chick foetal myoblast cultures. This shows that in addition to being a marker of connective tissue, OSR2 is also expressed in muscle fibres during chick development.

developmental biology↗

bioRxiv2017

Genome-wide strategies identify molecular niches regulated by connective tissue-associated transcription factors

BackgroundConnective tissues support, connect and separate tissues and organs, playing crucial roles in development, homeostasis and fibrosis. Cell specification and differentiation is triggered by the activity of specific transcription factors. While key transcription factors have been identified for differentiation processes of most tissues, connective tissue differentiation remains largely unstudied.\n\nResultsTo gain insight into the regulatory cascades involved in connective tissue differentiation, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in the differentiation of mesenchymal cells into connective tissue subtypes. We combined RNA-seq with ChIP-seq profiling in chick limb cells following overexpression of individual transcription factors. We identified a set of common genes regulated by all five transcription factors, which constitutes a connective tissue core expression set. This common core was enriched in genes associated with axon guidance and myofibroblast signature. In addition, each of the transcription factors regulated a different set of extracellular matrix components and signalling molecules, which define local molecular niches important for connective tissue development and function.\n\nConclusionsThe established regulatory network identifies common and distinct molecular signatures downstream of five connective tissue-associated transcription factors and provides insight into the signalling pathways governing limb connective tissue differentiation. It also suggests a concept whereby local molecular niches can be created via the expression of specific transcription factors impinging on the specification of microenvironments.

developmental biology↗

bioRxiv2017

A dual transcript-discovery approach to improve the delimitation of gene features from RNA-seq data in the chicken model

The sequence of the chicken genome, like several other draft genome sequences, is presently not fully covered. Gaps, contigs assigned with low confidence and uncharacterized chromosomes result in gene fragmentation and imprecise gene annotation. Transcript abundance estimation from RNA sequencing (RNA-seq) data relies on read quality, library complexity and expression normalization. In addition, the quality of the genome sequence used to map sequencing reads and the gene annotation that defines gene features must also be taken into account. Partially covered genome sequence causes the loss of sequencing reads from the mapping step, while an inaccurate definition of gene features induces imprecise read counts from the assignment step. Both steps can significantly bias interpretation of RNA-seq data. Here, we describe a dual transcript-discovery approach combining a genome-guided gene prediction and a de novo transcriptome assembly. This dual approach enabled us to increase the assignment rate of RNA-seq data by nearly 20% as compared to when using only the chicken reference annotation, contributing therefore to a more accurate estimation of transcript abundance. More generally, this strategy could be applied to any organism with partial genome sequence and/or lacking a manually-curated reference annotation in order to improve the accuracy of gene expression studies.

bioinformatics↗

bioRxiv2017

Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice

Beige adipocyte differentiation within white adipose tissue, referred to as browning, is seen as a possible mechanism for increasing energy expenditure. The molecular regulation underlying the thermogenic browning process has not been entirely elucidated. Here, we identify the zinc finger transcription factor EGR1 as a negative regulator of the beige fat program. Loss of Egr1 in mice promotes browning in the absence of external stimulation and activates Ucp1 that encodes the key thermogenic mitochondrial uncoupling protein-1. Moreover, EGR1 is recruited to the proximal region of the Ucp1 promoter in subcutaneous inguinal white adipose tissue. Transcriptomic analysis of subcutaneous inguinal white adipose tissue in the absence of Egr1 identifies the molecular signature of white adipocyte browning downstream of Egr1 deletion and highlights a concomitant increase of beige differentiation marker and decrease in extracellular matrix gene expression. Conversely, Egr1 overexpression in mesenchymal stem cells decreases beige adipocyte differentiation, while increasing extracellular matrix production. These results uncover the role of Egr1 in blocking energy expenditure via direct Ucp1 transcription regulation and highlight Egr1 as a therapeutic target for counteracting obesity.

developmental biology↗