Biology subjects

Fabiha, T.

Publications and source records attributed to Fabiha, T..

4 recordsLinked to original sources

bioRxiv2025

A stem cell knockout village reveals lineage rewiring and a non-canonical islet cell fate in monogenic diabetes

Genetics studies have identified a core set of regulators essential for pancreatic {beta} cell development, many of which are mutated in monogenic diabetes. However, how these mutations alter developmental trajectories to produce pathological cell states remains elusive. Here we introduce a knockout village framework that enables longitudinal scRNA-seq profiling of 79 human pluripotent stem cell mutant lines targeting 30 developmental regulators, including 15 diabetes genes, across five islet differentiation stages. We show that loss of lineage regulators impairs {beta} cell formation in a stage-specific manner and rewires developmental trajectories towards competing lineages. Notably, several monogenic diabetes gene mutations drive a shift from {beta} cells to enterochromaffin (EC)-like cells, a recently recognized non-canonical islet cell fate. These EC-like cells exhibit incomplete activation of hormone regulation programs, along with elevated neuron signatures. Leveraging the diversity of cell fate outcomes across mutants, we predicted and experimentally validated ISL1 as a key downstream effector of PDX1 and PAX6 that safeguards {beta} cell identity against an EC-like fate. Together, our findings reveal cell fate rewiring as a widespread, previously underappreciated pathological mechanism in monogenic diabetes and establish a scalable platform for uncovering developmental vulnerabilities in human genetic disorders.

developmental biology↗

bioRxiv2025

PRISM: ancestry-aware integration of tissue-specific genomic annotations enhances the transferability of polygenic scores

The limited transferability of polygenic scores (PGS) across populations constrains their clinical utility and risks exacerbating health disparities, given challenges in multi-ancestry training, fine-mapping, and variant prioritization using genomic annotations, particularly when biologically relevant reference resources are sparse or unavailable for the target population. Here, we introduce PRISM, a transfer learning approach that jointly addresses these challenges to enhance PGS transferability. Applying PRISM to 7352 fine-mapped variants, 414 ENCODE annotations, and 406,659 individuals from the UK Biobank, we demonstrate that ancestry-aware integration of tissue-specific annotations yields the largest gains in predictive performance for African ancestry, with an average improvement of 13.10% (p=1.6x10-5) over annotation-agnostic multi-ancestry PGS. Notably, the best-performing model uses 102-fold fewer annotations than non-specific models, with contributions from broad categories of annotations. Overall, PRISM complements ongoing data diversification efforts by providing an immediately applicable strategy based on the integration of biologically aligned, best-available resources to address genomic health equity.

genetics↗

bioRxiv2024

A consensus variant-to-function score to functionally prioritize variants for disease

Identifying and functionally characterizing causal disease variants in genome-wide association studies remains a pressing challenge. Here, we construct a consensus variant-to-function (cV2F) score that assigns a single value to each common single-nucleotide variant in the genome, and helps to predict and characterize causal disease variants. The cV2F score leverages features reflecting variant-level experimentally and computationally predicted function (e.g. allelic imbalance and sequence-based deep learning models) and element-level function (e.g. predicted enhancers), and learns optimal combinations of features by training a gradient boosting model on GWAS fine-mapping results. The cV2F-annotated variants attained an AUPRC of 0.822 at identifying held-out fine-mapped variants. Variants with high cV2F scores are highly enriched for heritability (14.2x, s.e. 0.5) across 66 diseases/traits, are uniquely informative for disease heritability, and are highly predictive of variants implicated by reporter assays; cV2F substantially outperforms previous variant-to-function scores using all of these metrics. GWAS fine-mapping of 110 diseases/traits informed by cV2F identified 14.3% more confidently fine-mapped (PIP > 0.95) variants than non-functionally informed fine-mapping. We further constructed tissue/cell line-specific cV2F scores that prioritize variants based on regulatory potential in specific tissues/cell lines, attaining high heritability enrichment for tissue-related diseases/traits (15.6x, s.e. 2.3) while providing independent information (average correlation of 0.27 with the primary cV2F score). We highlight examples of GWAS loci for which cV2F pinpoints causal variants with high confidence and elucidates their functional role.

genetics↗

bioRxiv2024

The Orphan G Protein-Coupled Receptor GPR52 is a Novel Regulator of Breast Cancer Multicellular Organization

Statement of SignificanceWe showed that loss of the orphan G protein-coupled receptor GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumor burden in zebrafish. BackgroundG protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors that transmit critical signals from extracellular to intracellular spaces. Transcriptomic data of resected breast tumors show that low mRNA expression of orphan GPCR GPR52 correlates with reduced overall survival in patients with breast cancer, leading to the hypothesis that loss of GPR52 supports breast cancer progression. MethodsCRISPR-Cas9 was used to knockout GPR52 in the human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line MCF10A. 2D and 3D in vitro studies, electron microscopy, Matrigel culture, and a zebrafish xenograft model were used to assess the morphology and behavior of GPR52 KO cells. RNA-sequencing and proteomic analyses were also conducted on these cell lines, and transcriptomic data from The Cancer Genome Atlas (TCGA) database were used to compare GPR52-null and wild-type (WT) signatures in breast cancer. ResultsLoss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells, and zebrafish injected with GPR52 KO cells developed a greater total cancer area than those injected with control cells. RNA sequencing and proteomic analyses of GPR52-null breast cancer cells revealed an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates the production of cAMP, induces phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some GPR52 KO phenotypes. ConclusionGPR52 is an orphan GPCR and its role in cancer progression has not been previously characterized. We found that GPR52 loss in breast cancer cells can lead to increased cell clustering, collective invasion, and EMT in vitro. These are features of increased cancer aggression. Our results reveal that GPR52 loss is a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option for breast cancer. O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/604482v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@8b0f55org.highwire.dtl.DTLVardef@19bd139org.highwire.dtl.DTLVardef@c52117org.highwire.dtl.DTLVardef@1ffa2bd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

cancer biology↗