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Infection by the Human Immunodeficiency Virus type 1 (HIV-1) remains a major global public health issue. Despite effective antiretroviral therapy, HIV-1 persistence occurs in cellular reservoirs, necessitating continuous drug intake leading HIV-1 infection into a chronic disease. Therefore, an HIV cure requires either eliminating these viral reservoirs or achieving an deep blockade of HIV-1 transcription in the absence of treatment. Deciphering the underlying molecular mechanisms that drive HIV-1 into latency is critical for targeted HIV cure efforts.This Ph.D. thesis aims to enhance the knowledge on the molecular mechanisms of HIV-1 latency, specifically at epigenetic level. First, this work contributes to the discovery of a novel epigenetic actor of HIV-1 latency, known as UHRF1, in both infected T-lymphoid and myeloid cells. UHRF1 acts as a HIV-1 transcriptional repressor by modulating both DNA and histone methylation. In addition to DNA methylation, many evidence have highlighted DNA hydroxymethylation as a new epigenetic mark involved in cellular transcriptional regulation. This Ph.D. thesis demonstrated the presence of DNA hydroxymethylation along both the latent and the reactivated HIV-1 provirus. Finally, this work led to the discovery of another novel epigenetic actor of HIV-1 latency, known as KLF16. This cellular transcription factor regulates HIV-1 transcription by modulating both histone acetylation and methylation in both the infected T-lymphocytic cell line and the infected monocytic cell line. Altogether, our findings expand our understanding of the molecular mechanisms involved in HIV-1 transcriptional latency, specifically at epigenetic level. Moreover, the identification of novel HIV-1 regulators have unveiled new drug targets that could be critical in HIV-1 cure efforts., Doctorat en Sciences, info:eu-repo/semantics/nonPublished

A highly evolved neocortex is associated with higher-order cognitive abilities humans possess. Thus, it is imperative to understand how the human cortex develops and its associated diseases. A complex network of transcription factors orchestrates the patterning of the cortex. Among them, Dmrt5 and Emx2 are evolutionarily conserved and are expressed early and similarly in the developing cortex. Interestingly, either of their deletions results in strikingly similar phenotypes and their compound deletion leads to an adverse phenotype, suggesting they cooperate during cortical development. During the first part of my PhD, I tried to understand the mechanisms at the basis of their cooperative function using mouse transgenics, bulk RNA sequencing, chromatin immunoprecipitation followed by sequencing and mass spectrometry-based methods. Our result suggests that their deletion perturbs a similar set of gene regulatory networks. Unexpectedly, their common direct targets are rather limited, but all encode important regulators of cortical fate. Exploration of their protein partners through mass spectrometry-based methods points to possible mechanisms contributing to their functional disparity, wherein they utilise a different set of interactors that confers their distinct functional properties. In the second part of my thesis, I also explored the unique role played by Dmrt5 in the development of the choroid plexus tissue, a brain-associated epithelial-endothelial convolute tissue that is involved in most of the cerebrospinal fluid production. The choroid plexus epithelium derives from the neuroepithelial tissue, which selectively expresses Dmrt5 as opposed to Emx2. Dmrt5 conditional ablation in the medial pallium does not result in any identifiable specification defects of the choroid plexus. Yet, mice in which Dmrt5 is conditionally deleted postnatally develop hydrocephalous, a condition often linked with defective choroid plexus function. Results obtained suggest that this p, Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Translational regulation is of paramount importance for proteome remodeling during stem cell differentiation at both the global and the transcript-specific levels. In this study, we characterized translational remodeling during hepatogenic differentiation of induced pluripotent stem cells (iPSCs) by polysome profiling. We demonstrate that protein synthesis increases during exit from pluripotency and is then globally repressed during later steps of hepatogenic maturation. This global downregulation of translation is accompanied by a decrease in the abundance of protein components of the translation machinery, which involves a global reduction in translational efficiency of terminal oligopyrimidine tract (TOP) mRNA encoding translation-related factors. Despite global translational repression during hepatogenic differentiation, key hepatogenic genes remain efficiently translated, and the translation of several transcripts involved in hepatospecific functions and metabolic maturation is even induced. We conclude that, during hepatogenic differentiation, a global decrease in protein synthesis is accompanied by a specific translational rewiring of hepatospecific transcripts.

info:eu-repo/semantics/nonPublished

Translational regulation is of paramount importance for proteome remodeling during stem cell differentiation at both the global and the transcript-specific levels. In this study, we characterized translational remodeling during hepatogenic differentiation of induced pluripotent stem cells (iPSCs) by polysome profiling. We demonstrate that protein synthesis increases during exit from pluripotency and is then globally repressed during later steps of hepatogenic maturation. This global downregulation of translation is accompanied by a decrease in the abundance of protein components of the translation machinery, which involves a global reduction in translational efficiency of terminal oligopyrimidine tract (TOP) mRNA encoding translation-related factors. Despite global translational repression during hepatogenic differentiation, key hepatogenic genes remain efficiently translated, and the translation of several transcripts involved in hepatospecific functions and metabolic maturation is even induced. We conclude that, during hepatogenic differentiation, a global decrease in protein synthesis is accompanied by a specific translational rewiring of hepatospecific transcripts., SCOPUS: ar.j, info:eu-repo/semantics/published

Nowadays, life expectancy is increasing but is not systematically accompanied by a decent quality of life during aging. With the overall aging of the population, it is urgent to highlight strategies to promote the maintenance of autonomy at old age. While the effects of exercise training on limiting the loss of functional autonomy in the elderly are well-established, the molecular mechanisms by which it may slowdown the hallmarks of skeletal muscle aging, notably through the regulation of telomere health and cellular senescence, need to be further investigated. In this thesis, we found that even if endurance training did not effectively reduce senescence, the training status might attenuate the senescence-associated secretory phenotype in human skeletal muscle. Moreover, the age-dependent increase in TERRA expression might represent a novel biological marker of aging which is alleviated by endurance training., (MOTR - Sciences de la motricité) -- UCL, 2022

info:eu-repo/semantics/published

Mitochondrial uncoupling can be defined as a dissociation between mitochondrial membrane potential generation and its use for mitochondria-dependent ATP synthesis. Although this process was originally considered a mitochondrial dysfunction, the identification of UCP-1 as an endogenous physiological uncoupling protein suggests that the process could be involved in many other biological processes. In this review, we first compare the mitochondrial uncoupling agents available in term of mechanistic and non-specific effects. Proteins regulating mitochondrial uncoupling, as well as chemical compounds with uncoupling properties are discussed. Second, we summarize the most recent findings linking mitochondrial uncoupling and other cellular or biological processes, such as bulk and specific autophagy, reactive oxygen species production, protein secretion, cell death, physical exercise, metabolic adaptations in adipose tissue, and cell signaling. Finally, we show how mitochondrial uncoupling could be used to treat several human diseases, such as obesity, cardiovascular diseases, or neurological disorders., SCOPUS: re.j, info:eu-repo/semantics/published

Mitochondria are complex organelles that participate in many cellular functions, ranging from ATP production to immune responses against viruses and bacteria. This integration of a plethora of functions within a single organelle makes mitochondria a very attractive target to manipulate for intracellular pathogens. We characterised the crosstalk that exists between Brucella abortus, the causative agent of brucellosis, and the mitochondria of infected cells. Brucella replicates in a compartment derived from the endoplasmic reticulum (ER) and modulates ER functionality by activating the unfolded protein response. However, the impact of Brucella on the mitochondrial population of infected cells still requires a systematic study. We observed physical contacts between Brucella containing vacuoles and mitochondria. We also found that B. abortus replication is independent of mitochondrial oxidative phosphorylation and that mitochondrial reactive oxygen species do not participate to the control of B. abortus infection in vitro. We demonstrated that B. abortus and B. melitensis induce a drastic mitochondrial fragmentation at 48 hours post-infection in different cell types, including myeloid and non-myeloid cells. This fragmentation is DRP1-independent and might be caused by a deficit of mitochondrial fusion. However, mitochondrial fragmentation does not change neither Brucella replication efficiency, nor the susceptibility of infected cells to TNFα-induced apoptosis., SCOPUS: ar.j, info:eu-repo/semantics/published

Increasing evidence supports that modifications in the mitochondrial content, oxidative phosphorylation (OXPHOS) activity, and cell metabolism influence the fate of stem cells. However, the regulators involved in the crosstalk between mitochondria and stem cell fate remains poorly characterized. Here, we identified a transcriptional regulatory axis, composed of transcription factor 7-like 2 (TCF7L2) (a downstream effector of the Wnt/β-catenin pathway, repressed during differentiation) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) (the master regulator of mitochondrial biogenesis, induced during differentiation), coupling the loss of pluripotency and early commitment to differentiation, to the initiation of mitochondrial biogenesis and metabolic shift toward OXPHOS. PGC-1α induction during differentiation is required for both mitochondrial biogenesis and commitment to the hepatocytic lineage, and TCF7L2 repression is sufficient to increase PGC-1α expression, mitochondrial biogenesis and OXPHOS activity. We further demonstrate that OXPHOS activity is required for the differentiation toward the hepatocytic lineage, thus providing evidence that bi-directional interactions control stem cell differentiation and mitochondrial abundance and activity. Stem Cells 2017;35:2184–2197., SCOPUS: ar.j, info:eu-repo/semantics/published