Biology subjects

Ibrahim, D.

Publications and source records attributed to Ibrahim, D..

3 recordsLinked to original sources

bioRxiv2025

Endothelial CEPT1 Regulates Hepatic MTTP-Mediated Lipid Metabolism and Impacts Aortic Atherosclerosis

BackgroundThe regulation of hepatic lipid metabolism by vascular endothelial factors remains poorly characterized, despite its relevance to atherosclerosis and steatosis. Microsomal triglyceride transfer protein (MTTP) is essential for hepatic lipid metabolism, but its regulation by endothelial cells has not been previously investigated. ObjectiveThis study examined whether endothelial choline ethanolamine phosphotransferase 1 (CEPT1) modulates hepatic MTTP activity, impacting systemic lipid homeostasis and aortic plaque formation. Methods and ResultsHuman steatotic liver samples exhibited reduced CEPT1 and MTTP protein levels, correlating with diminished lipid exports. In mice, endothelial-specific Cept1 knockdown decreased hepatic MTTP expression, reduced serum triglyceride and cholesterol levels, and markedly attenuated aortic atherosclerosis without evidence of fat malabsorption. In vitro, endothelial CEPT1 silencing suppressed MTTP activity in co-cultured hepatocytes via a paracrine mechanism involving peroxisome proliferator-activated receptor (PPAR) signaling, which was rescued by fenofibrate treatment. Aortic histology confirmed reduced plaque burden and macrophage infiltration in CEPT1-deficient mice. ConclusionsEndothelial CEPT1 critically regulates hepatic MTTP through a paracrine axis, influencing lipid metabolism and atherogenesis. Targeting endothelial CEPT1 may represent a novel therapeutic approach to reduce steatosis and vascular atherosclerosis.

molecular biology↗

bioRxiv2022

Single cell, whole embryo phenotyping of pleiotropic disorders of mammalian development

Mouse models are a critical tool for studying human diseases, particularly developmental disorders, as well as for advancing our general understanding of mammalian biology. However, it has long been suspected that conventional approaches for phenotyping are insufficiently sensitive to detect subtle defects throughout the developing mouse. Here we set out to establish single cell RNA sequencing (sc-RNA-seq) of the whole embryo as a scalable platform for the systematic molecular and cellular phenotyping of mouse genetic models. We applied combinatorial indexing-based sc-RNA-seq to profile 101 embryos of 26 genotypes at embryonic stage E13.5, altogether profiling gene expression in over 1.6M nuclei. The 26 genotypes include 22 mouse mutants representing a range of anticipated severities, from established multisystem disorders to deletions of individual enhancers, as well as the 4 wildtype backgrounds on which these mutants reside. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibited changes in dozens of trajectories (e.g., the pleiotropic consequences of altering the Sox9 regulatory landscape) whereas others showed phenotypes affecting specific subsets of cells. We also identify differences between widely used wildtype strains, compare phenotyping of gain vs. loss of function mutants, and characterise deletions of topological associating domain (TAD) boundaries. Intriguingly, even among these 22 mutants, some changes are shared by heretofore unrelated models, suggesting that developmental pleiotropy might be "decomposable" through further scaling of this approach. Overall, our findings show how single cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

genomics↗

bioRxiv2021

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution. HIGHLIGHTSO_LINew genes can emerge in evolution without taking on the expression pattern of their surrounding pre-existing TAD. C_LIO_LICompartmentalisation can restructure seemingly evolutionarily stable TADs to control a promoters access to enhancers. C_LIO_LILamina-associated domains neither prevent transcriptional activation nor enhancer-promoter communication. C_LIO_LIRepression rather than promoter-specificity refines when genes respond to promiscuous enhancer activities in specific tissues. C_LI

genetics↗