Biology subjects

Messiaen, S.

Publications and source records attributed to Messiaen, S..

5 recordsLinked to original sources

bioRxiv2024

Genome-wide transcriptional silencing and mRNA stabilization allow the coordinated expression of the meiotic program in mice

The transcriptional dynamic of mammalian cells when these transit from the ubiquitous mitotic to a meiotic specific program is key to understand this switch central to sexual reproduction. By quantifying active RNA polymerase II and nascent transcripts using single cell dataset and ethynyl-uridine pool-down with sorted cells from synchronised testes, we detailed the transcriptional activity of murine male germ cells. When spermatogonia differentiate, transcription slows down, reaching minimal activity at meiotic entry and resumes during pachytene stage. This event, we termed EMLT (for early meiotic low transcription), is distinct from the silencing of sex chromosomes as it is independent of Setdb1 though it is accompanied by the same chromatin mark, H3K9me3. EMLT is delayed in Stra8KO but occurs in mutants altering meiotic chromosome structure or DSB formation or repair. By comparing transcript abundance and neotranscription we unveil a massive event of mRNA stabilization that parallels EMLT. Altogether our data indicate that meiosis is initiated with a nearly silent genome and we propose that the stabilization of transcripts at that time facilitates the meiotic entry by synchronising the expression of several meiotic sub-programs.

cell biology↗

bioRxiv2023

Evidence of the ability of endocrine disrupting compounds to induce testicular germ cell cancer in humans.

Testicular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.

cancer biology↗

bioRxiv2023

Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne(R), a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne(R) also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne(R) had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne(R) as a potent therapeutic agent of COVID-19 symptomatology. Author SummaryAccumulating evidence shows that oxidative stress coupled with the systemic inflammation contribute to COVID-19 pathogenesis. As the Keap1/Nrf2 pathway is the major regulator of redox homeostasis and promotes resolution of inflammation and as lung biopsies from COVID-19 patients showed a decreased NRF2 target gene signature, pharmacological agents that are known to activate NRF2 are good candidates for COVID-19 treatment. We show herein that Sulfodyne(R), an NRF2 activator that consists in a stabilized Sulforaphane preparation with optimal bioavailability, impairs SARS-CoV-2 replication in colonic or pulmonary epithelial cells. We show that this antiviral activity of Sulfodyne(R) is not dependent of NRF2 activation, characterize the pathways associated with the Sulfodyne(R) antiviral activity and show that Sulfodyne(R) displays multiple actions that result in a decrease of the inflammation associated with SARS-CoV-2 infection. Finally, we show that Sulfodyne(R) decreases the pathogenesis of mice or hamster infected with SARS-CoV-2. Overall, this study provides mechanistic explanations of the action of Sulfodyne(R) during SARS-CoV-2 infection and suggests that Sulfodyne(R) is a potential therapeutic agent of COVID-19 pathogenesis.

cell biology↗

bioRxiv2020

DNA oxidation induced by fetal exposure to BPA agonists impairs female meiosis

Many endocrine disruptors have been proven to impair the meiotic process that is mandatory to produce healthy gametes. Bisphenol A is emblematic as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing uses of BPA analogs raise concerns for public health. Here, we investigated the effect on oogenesis in mouse of fetal exposure to two BPA analogs, Bisphenol A Diglycidyl Ether (BADGE) or Bisphenol AF (BPAF). These analogs delay meiosis initiation, increase MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by a deregulation of gene expression and aberrant mRNA splicing in fetal premeiotic germ cells. Interestingly, we observed an increase in DNA oxidation after exposure to BPA analogs. Specific induction of oxidative DNA damages during fetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-Oxoguanine DNA Glycosylase (OGG1) deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damages. Moreover, the supplementation of N-acetylcysteine (NAC) with BPA analogs counteracts the bisphenol-induced meiotic effect. Together our results position oxidative stress as a central event that negatively impacts the female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for so called endocrine disruptors pollutants and it could lead to novel strategies for reprotoxic compounds.

molecular biology↗

bioRxiv2019

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits.

Primary Ovarian insufficiency (POI) affects 1% of women under forty. We studied a patient with a non-syndromic POI, from a consanguineous Turkish family. Exome sequencing identified a homozygous missense variant c.8524C>T/p.R2842C in BRCA2. BRCA2 is a major player in homologous recombination (HR). BRCA2 deficiency induces cancer predisposition and Fanconi Anemia (FA). Remarkably, neither the patient nor her family exhibit somatic pathologies. The patients somatic cells presented intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation when compared to controls, the heterozygous mothers and FA cells. R2842C-BRCA2 partially complemented BRCA2 depletion for double-strand break-induced HR. The residual HR function in patients cells could explain the absence of somatic pathology. BRCA2 is expressed in human fetal ovaries in pachytene stage oocytes, when meiotic HR occurs. This study has a major impact on the understanding of genome maintenance in somatic and meiotic cells and on the management of POI patients.

genetics↗