Adinolfi, M. | Search bioRxiv

bioRxiv2023

Investigating mitochondrial gene expression patterns in Drosophila melanogaster using network analysis to understand aging mechanisms

The process of aging is a complex phenomenon that involves a progressive decline in physiological functions required for survival and fertility. To better understand the mechanisms underlying this process, the scientific community has utilized several tools. Among them, mitochondrial DNA has emerged as a crucial factor in biological aging, given that mitochondrial dysfunction is thought to significantly contribute to this phenomenon. Additionally, Drosophila melanogaster has proven to be a valuable model organism for studying aging due to its low cost, capacity to generate large populations, and ease of genetic manipulation and tissue dissection. Moreover, graph theory has been employed to understand the dynamic changes in gene expression patterns associated with aging and to investigate the interactions between aging and aging-related diseases. In this study, we have integrated these approaches to examine the patterns of gene co-expression in Drosophila melanogaster at various stages of development. By applying graph-theory techniques, we have identified modules of co-expressing genes, highlighting those that contain a significantly high number of mitochondrial genes. We found important mitochondrial genes involved in aging and age-related diseases in Drosophila melanogaster, including UQCR-C1, ND-B17.2, ND-20, and Pdhb. Our findings shed light on the role of mitochondrial genes in the aging process and demonstrate the utility of Drosophila melanogaster as a model organism and graph theory in aging research.

bioinformatics↗

bioRxiv2022

High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors

Obesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RAR oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA in the hematopoietic system (PML-RAR KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RAR KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RAR this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RAR HPCs by activating the peroxisome proliferator-activated receptor delta (PPAR{delta}), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity. Key pointsO_LIhigh fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humans C_LIO_LIalthough HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPAR{delta} C_LI

cancer biology↗