Biology subjects

Personnaz, J.

Publications and source records attributed to Personnaz, J..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary and biological insights into the paternally expressed Snord116-Ipw-Snord115 gene array at the imprinted Prader-Willi syndrome domain

Placental mammal-specific box C/D small nucleolar RNA (SNORD) genes within the imprinted human 15q11q13 domain have garnered increasing attention because their poorly understood roles in the brain and their potential involvement in Prader-Willi syndrome (PWS). Using two novel knockout (KO) mouse models, we demonstrate that combined deletion of Snord116 and Snord115 genes, but not the intervening Ipw ncRNA gene, leads to partially penetrant perinatal lethality (40-50%). Snord116/115-deficient neonates display postnatal growth impairment, hypoglycemia and endocrine dysregulation, including failure of the postnatal leptin surge. Despite showing no overt alterations in feeding behavior, adult Snord116/115-KO mice recapitulate most phenotypes previously reported in Snord116-KO models. RNA-seq analyses of the hypothalamus, prefrontal cortex and cerebellum reveal limited global changes. However, we observed upregulation of two of the most compelling putative RNA targets of Snord116 and Snord115 (Dgkk and Htr2c, respectively) in the postnatal hypothalamus. Nevertheless, no evidence was found to support efficient Snord115-guided ribose methylation of Htr2c mRNA. Finally, comparative analyses across 64 representative placental mammal species reveal that many PWS-associated SNORD genes, including SNORD115, display greater evolutionary changes than previously appreciated, raising questions about the functional relevance and evolutionary selective pressures that have shaped the diversification of certain family members across species. Overall, our study provides an unbiased re-assessment of the evolutionary, molecular and physiological significance of the paternally expressed Snord116-Ipw-Snord115 genomic interval and highlights the early postnatal period as a critical, yet largely underexplored, developmental window during which recently evolved SNORDs likely function as dispensable fine-tuners of gene expression.

genetics↗

bioRxiv2024

Testing the contribution of fibrinogen like 1 to the pathogenesis of metabolic dysfunction associated steatotic liver disease and hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with simple steatosis, which can progress to hepatocellular carcinoma (HCC). The pathogenesis of MASLD alters the secretion of hepatokines such as fibrinogen-like 1 (FGL1), a candidate mediator of liver steatosis and hyperglycemia. To investigate the contribution of FGL1 to liver diseases, we compared wild-type mice to mice with hepatocyte-specific deletion of Fgl1 subjected to a steatosis or HCC experimental protocol. We found that mice deficient for Fgl1 in hepatocytes showed higher levels of plasma glucose, pronounced metabolic alterations and liver injury when fed a western diet compared to their wild-type counterparts. However, both genotypes exhibited a similar lipid deposition in the liver. Similarly, wild type and Fgl1-deficient mice displayed comparable liver alterations during HCC progression. We observed that FGL1 expression was repressed during MASLD progression in mice and human concomitantly with the severity of liver injury. Altogether, these findings suggest that FGL1 is not a major contributor to the pathogenesis of MASLD and HCC.

pathology↗

bioRxiv2024

AKT-mediated phosphorylation of TSC2 controls stimulus and tissue-specific mTORC1 signaling and organ growth

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse intracellular and extracellular growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling established through biochemical and cell biological studies function under physiological states in specific mammalian tissues are unknown. Here, we characterize a genetic mouse model lacking the 5 phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can active mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as brain and skeletal muscle, associated with cell intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mouse model demonstrates that TSC2 phosphorylation is a primary mechanism of mTORC1 activation in some, but not all, tissues and provides a genetic tool to facilitate studies on the physiological regulation of mTORC1.

cell biology↗

bioRxiv2021

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXR activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXR. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXR axis during NAFLD.

pathology↗