Biology subjects

Krifa, S.

Publications and source records attributed to Krifa, S..

4 recordsLinked to original sources

bioRxiv2025

Exploring cardiac phenotypes of Drosophila orthologues of human genes associated to Brugada Syndrome (BrS)

Brugada syndrome (BrS) is a rare cardiac arrhythmic disorder with high risk of sudden cardiac death. Recent advances have identified more than 20 risk loci with complex inheritance suggesting a polygenic model for BrS inheritance. These loci are in non-coding regions located in the vicinity of cardiac-expressed genes. This complex genetic architecture and the limited understanding of BrS genetic and molecular mechanisms hinder the development of efficient prevention strategies in the context of this syndrome and are unfavorable to the implementation of therapeutic interventions. In this context, understanding the functional impact of the identified putative risk alleles is a prerequisite. Here, we used the fly model to systematically test whether orthologues of genes located near risk alleles for BrS participate to cardiac function. The fly is the simplest model with a heart muscle and is a powerful genetic model suitable for efficient screening of candidate genes, providing a whole organism-based assessment of cardiac development, structure and function. Using high-speed heart imaging platform on intact flies, we invalided the cardiac expression of the fly orthologues of human genes associated to BrS and characterized whether they are cell autonomously implicated in heart functioning. Our results provide an overview of cardiac phenotypes associated with genes potentially involved in BrS, enabling their prioritization for further investigations in mammalian models.

genetics↗

bioRxiv2024

Metabolism fine tuning and cardiokines secretion represent adaptative responses of the heart to High Fat and High Sugar Diets in flies

Cardiopathies are one of the leading causes of death in obese diabetics. Diabetic cardiomyopathies are notably characterized by contractile dysfunctions. Using the Drosophila model for cardiac function in pathophysiological context, we identified a set of candidate genes whose cardiac expression is modulated by High Sugar and High Fat regimes. Genes encoding core components of key homeostatic pathways - such as 1C-metabolism homeostasis, the Galactose metabolism pathway and metabolites transporters - were identified and characterized as adaptative factors of cardiac function under nutritional stresses. In addition, putative secreted proteins were found dysregulated, highlighting the heart as a secretory organ in hyperglycemia and hyperlipidemia. In particular, we characterized the Fit satiety hormone as a new fly cardiokine, which autonomously modulates the cardiac function and remotely affects feeding behavior. Overall, our study uncovered autonomous and systemic adjustable responses of the heart to nutritional stresses.

physiology↗

bioRxiv2024

Natural variations of aging of cardiac performance in Drosophila identifies a central function for the PAR domain bZIP transcription factor Pdp1/dHLF in cardiac senescence

The identification of genetic factors influencing cardiac senescence in natural populations is central to our understanding of cardiac aging and to identify the etiology of associated cardiac disorders in human populations. However, the genetic underpinning of complex traits in human is almost impossible, due to the infeasibility to control genetic background and gene-environment interactions. Drosophila has striking similarities in cardiac aging with humans, highlighting the conserved nature of cardiac aging for organisms with a heart. Leveraging on a large collection of inbred lines from the Drosophila Genetic Reference Panel (DGRP), we provide an accurate analysis of cardiac senescence in a natural population of flies. This permitted the discovery of an unprecedented number of variants and associated genes significantly associated to the natural variation of cardiac aging. We focused on the function of the PAR-domain bZIP transcription factor Pdp1 for which several variants were found associated with natural variation of the aging of multiple cardiac functional traits. We demonstrated that Pdp1 cell autonomously plays a central role in cardiac senescence and might do so by regulating mitochondria homeostasis. Overall, our work provides a unique resource regarding the genetics of cardiac aging in a natural population.

genetics↗

bioRxiv2021

Genetic architecture of natural variations of cardiac performance in flies

Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome Wide Associations Studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict Transcription Factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.

genetics↗