Biology subjects

Gerges, P.

Publications and source records attributed to Gerges, P..

4 recordsLinked to original sources

bioRxiv2025

Expanding the DNA Motif Lexicon of the Transcriptional Regulatory Code

Transcriptional regulatory sequences in metazoans contain intricate combinations of transcription factor (TF) motifs. Stereospecific arrangements of simple motifs constitute composite elements (CEs) that enhance DNA-protein interaction specificity and enable combinatorial regulatory logic. Despite their importance, CEs remain underexplored. We advance CE discovery and functional characterization by developing an integrated framework that combines computational prediction, experimental testing and deep learning. The extended TF motif catalog comprises both synergistic and counteracting CEs, which are supported by evidence of TF binding in vivo and in vitro. A deep learning model GRACE trained on customized massively parallel reporter assays learns the lexicon of CEs at single-nucleotide resolution. Comparative analysis with a neural network model trained on chromatin accessibility demonstrates striking convergence and distinctions within the expanded regulatory lexicon, enabling joint predictions of motif contributions and the impact of variants on chromatin structure and transcriptional activity in diverse cellular contexts.

genomics↗

bioRxiv2025

Cell cycle-coupled transcriptional network orchestrates human B cell fate bifurcation

Bifurcation of activated human B cells into plasmablast (PB) and germinal center precursor (preGC) fates underlies protective and autoimmune antibody responses, yet gene regulatory networks (GRNs) governing the alternative trajectories remain poorly defined. Using temporal single-cell multiomics, we assembled state-specific human B cell GRNs spanning four scales: transcription factor (TF)-to-fate, TF-to-gene, cis-regulatory element (CRE)-to-gene and nucleotide-to-CRE. Applying the framework to in vitro differentiated and tonsil B cells revealed concordant regulatory architectures and impacts of in silico TF perturbations. CRISPR perturbations validated many TF-to-fate and TF-to-gene predictions and revealed a mutually repressive BATF-IRF4/PRDM1 network module. The GRNs were used to predict and interpret effects of autoimmune disease variants, uncovering partitioning of disease risk at distinct TF motifs and B cell states. Predicted functional variants were independently supported by chromatin and expression QTLs and reporter assays. A web application enables exploration of B cell regulatory determinants of vaccine responses and autoimmune diseases.

immunology↗

bioRxiv2024

Altered AP-1, RUNX, and EGR chromatin dynamics drive fibrotic lung disease

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1hi macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.

systems biology↗

bioRxiv2024

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

How stem and progenitor cells give rise to multiple cell types in defined numbers and proportions is a central question in developmental biology. Epigenetic switches, acting at single gene loci, can generate extended delays in the activation timing of lineage-specifying genes, and thereby impact lineage decisions and cell type output of progenitors. Here, we analyzed a timed epigenetic switch controlling Bcl11b, a transcription factor that drives T cell lineage commitment, but only after a long multi-day time delay in expression. To investigate roles for this delay in controlling lineage decision making, we analyzed progenitors with a deletion in a distal Bcl11b enhancer, that further extends this delay by [~]3 days. Strikingly, delaying Bcl11b activation reduces T cell output but enhances ILC generation in the thymus, and does so by redirecting progenitors to the ILC lineages at the T and ILC developmental branchpoint. Mechanistically, delaying Bcl11b activation promoted ILC redirection by up-regulating a PLZF-dependent ILC transcriptional program in progenitors. Despite up-regulating PLZF, committed ILC progenitors were still capable of later activating Bcl11b, which is also needed for specification of type 2 ILCs. These results show that epigenetic switches, by controlling the activation timing and order of lineage-specifying genes within regulatory networks, can modulate population sizes and proportions of differentiated cell types.

developmental biology↗