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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

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