Biology subjects

Fachal, L.

Publications and source records attributed to Fachal, L..

4 recordsLinked to original sources

bioRxiv2026

An integrated multimodal pan-organ atlas of the female reproductive system across the lifespan contextualises gynaecological pathologies

Single cell transcriptomics has transformed our knowledge of reproductive tissues, yet studies remain largely organ-specific and temporally limited, leaving an incomplete picture of how cell types are distributed across the reproductive system over a lifetime. Gynaecological conditions affect more than one in four females and frequently span multiple organs and life stages. To advance our understanding and treatment of these conditions, an integrated cellular reference is essential. Here we present the Human Female Reproductive System Cell Atlas v1: a single-cell transcriptomic resource integrating more than 2M cells across the ovary, fallopian tube, uterus, cervix and vagina over the lifespan and menstrual cycle, further integrated with spatial transcriptomics and chromatin accessibility profiling to define 210 cell types through community-based annotation. Cross-organ integration resolves shared and organ-specific cellular states, identifying uterine-specific perivascular populations lining uterine spiral arteries, hypoxia-sensing type 3 innate lymphoid cells (ILC3s) enriched in the uterus, and lipid-associated macrophages with distinct subsets in each reproductive organ, including a previously undescribed population shared between the uterus and fallopian tube. Cross-organ integration enables detection of ectopic epithelial populations in otherwise healthy donors, including endometrial-like cells within a paediatric ovary consistent with early endometriosis. Integration with genome-wide association studies (GWAS) reveals that risk variants for major gynecological conditions act in mesenchymal cell states defined by specific transcriptional programmes and spatial or temporal context - for instance, heavy menstrual bleeding risk is enriched in basal fibroblasts (SFRP5) of the regenerative endometrial compartment. An integrated chromatin accessibility atlas provides peak-to-gene maps across reproductive cell types, enabling nomination of disease effector genes and providing the first regulatory evidence linking a Polyendocrine Metabolic Ovarian Syndrome (PMOS) risk locus to INHBB in granulosa cells. Together, this resource establishes a cellular and molecular framework for reproductive biology and the pathogenesis of neglected gynaecological conditions.

Cell Biology↗

bioRxiv2019

Chromatin interactome mapping at 139 independent breast cancer risk signals

Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals, and explore the functional mechanism underlying altered risk at the 12q24 risk region. Our results demonstrate the power of combining genetics, computational genomics and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

molecular biology↗

bioRxiv2019

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

Fine-mapping of breast cancer GWAS regions has identified 195 high confidence signals containing more than 5,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements and thus may confer the risk by altering gene expression in cis. We analyzed allelic expression imbalance (AEI) of genes surrounding known breast cancer signals, using normal breast and breast tumor transcriptome data and imputed genotypes. Fourteen genes, including NTN4, were identified whose expression was associated with CCV genotype. We showed that CCVs at this signal were located within an enhancer that physically interacts with the NTN4 promoter. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. Here, we present the most comprehensive AEI analysis of breast cancer CCVs resulting in identification of new candidate risk genes.

genetics↗

bioRxiv2019

Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

genetics↗