Biology subjects

Richard, Q.

Publications and source records attributed to Richard, Q..

3 recordsLinked to original sources

bioRxiv2024

The oncometabolite D-2-hydroxyglutarate promotes DNA hypermethylation at lineage-specific enhancers controlling microglial activation in IDHmut gliomas

Tumor-associated microglia and macrophages (TAMs), the most abundant myeloid populations in gliomas, shape immune responses through transcriptional programs influenced by the tumor microenvironment. Although these programs differ according to tumor IDH status, the underlying epigenetic mechanisms remain poorly understood. Here, we uncover widespread DNA hypermethylation in the myeloid compartment of IDH-mutant gliomas, predominantly at distal enhancers enriched for motifs of core microglial transcription factors (TFs). This remodeled enhancer landscape strongly correlated with reduced activity of TF regulons and coordinated repression of immunomodulatory programs that normally support microglial activation. Using primary human microglia, we show that prolonged exposure to the oncometabolite D-2-hydroxyglutarate (D-2HG) reduces TET activity and increases 5mC/5hmC ratios near TF-binding motifs within enhancers affected ex vivo. Consistent with these epigenetic alterations, D-2HG-treated microglia exhibited transcriptional signatures compatible with blunted proinflammatory responses, whereas pharmacological inhibition of mutant IDH in patients partially restored microglial immune reactivity. Altogether, our findings reveal a chronic D-2HG-driven epigenetic priming mechanism that promotes a hyporesponsive microglial state, providing a rationale for the immunologically cold phenotype of IDH-mutant gliomas and offering insight into how IDH-targeted therapies may reshape microglial immune responses.

cancer biology↗

bioRxiv2024

Developmental alterations of indirect-pathway medium spiny neurons in mouse models of Huntington's disease.

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the Huntingtin protein (Htt). While symptoms, primarily characterized by progressive deterioration of the striatum and motor and cognitive functions, typically manifest in adulthood, recent studies have also highlighted developmental defects in HD. Indeed, alterations in cortical and striatal development have been observed in individuals carrying the mutation as early as in embryonic stages. However, despite the striatum being one of the most affected regions in HD, few studies have investigated potential developmental alterations in this structure, especially in the early weeks after birth. To address this question, we compared striatal development between wild-type (WT) mice and two murine models of HD, R6/1 and CAG140 mice crossed with reporter mice to identify D1- and D2-expressing medium spiny neurons (D1- and D2-MSNs). Using ex vivo electrophysiology and neuronal reconstruction, we observed that the maturation of electrical properties was selectively disrupted in D2-MSNs of the matrix compartment of HD mice during the first post-natal days. D2-MSNs arbor also an increased dendritic complexity. When studying the establishment of striatal afferents, we observed that cortico-striatal glutamatergic transmission was specifically reduced in D2-MSNs during the second postnatal week. All these alterations were transient before the circuit normalized on its own after the second postnatal week. These anatomical and electrophysiological data highlight the significant impact of the Htt mutation on numerous striatal development processes during the postnatal period. Interestingly, we observed that these alterations specifically affect MSNs in the indirect pathway. This preferential vulnerability aligns with the early death of these neurons in adulthood, suggesting that early treatment of these alterations could potentially modify the diseases progression.

neuroscience↗

bioRxiv2023

Mosquito aging modulates the development, virulence and transmission potential of pathogens

Host age variation is a striking source of heterogeneity that can shape the evolution and transmission dynamic of pathogens. Compared to vertebrate systems, our understanding of the impact of host age on invertebrate-pathogen interactions remains limited. We examined the influence of mosquito age on key life-history traits driving human malaria transmission. Females of Anopheles coluzzii, a major malaria vector, belonging to three age classes (4, 8, and 12 day-old), were experimentally infected with Plasmodium falciparum field isolates. Our findings revealed reduced competence in 12-day-old mosquitoes, characterized by lower oocyst/sporozoite rates and intensities compared to younger mosquitoes. Despite shorter median longevities in older age classes, infected 12-day-old mosquitoes exhibited improved survival, suggesting that the infection might act as a fountain of youth for older mosquitoes specifically. The timing of sporozoite appearance in the salivary glands remained consistent across mosquito age classes, with an extrinsic incubation period of approximately 13 days. Integrating these results into an epidemiological model revealed a lower vectorial capacity for older mosquitoes compared to younger ones, albeit still substantial due to extended longevity in the presence of infection. Considering age heterogeneity provides valuable insights for ecological and epidemiological studies, informing targeted control strategies to mitigate pathogen transmission.

ecology↗