Biology subjects

Pagie, L.

Publications and source records attributed to Pagie, L..

3 recordsLinked to original sources

bioRxiv2026

A high-resolution atlas of cattle regulatory variants and their cross-species activity in matched human cells

Identifying causal noncoding variants underlying complex traits in cattle remains challenging because high-resolution functional maps of regulatory variation are lacking. Here we combine massively parallel reporter assays with graph genomics to measure autonomous transcriptional activity from >1.5 billion DNA fragments spanning both cattle subspecies. In primary bovine cells, we assay >15 million variants and identify >150,000 expression-modulating variants enriched at cattle eQTL and GWAS loci. This enables the refinement of broad association signals to small sets of candidate functional regulatory variants. Our haplotype-aware framework captures rare, multi-allelic and tightly linked variants poorly resolved by conventional eQTL studies, and quantifies the disproportionate impact of larger variants on transcription. Furthermore, we use these data to train a deep-learning model that successfully predicts bovine promoter activity directly from sequence. Profiling the same cattle DNA in matched primary human cells reveals widespread conservation of promoter and enhancer activity, allelic effects and regulatory grammar, supporting the transfer of annotations and models across species. However, species-dependent effects are enriched in evolutionarily young sequences and p53-family motifs, highlighting the limits to simple cross-species extrapolation. Together, these data provide a high-resolution atlas of cattle regulatory variation and a framework for prioritising causal noncoding variants for cattle trait improvement.

genetics↗

bioRxiv2018

Promoter-intrinsic and local chromatin features determine gene repression in lamina-associated domains

It is largely unclear whether genes that are naturally embedded in lamina associated domains (LADs) are inactive due to their chromatin environment, or whether LADs are merely secondary to the lack of transcription. We show that hundreds of human promoters become active when moved from their native LAD position to a neutral context in the same cells, indicating that LADs form a repressive environment. Another set of promoters inside LADs is able to \"escape\" repression, although their transcription elongation is attenuated. By inserting reporters into thousands of genomic locations, we demonstrate that these escaper promoters are intrinsically less sensitive to LAD repression. This is not simply explained by promoter strength, but by the interplay between promoter sequence and local chromatin features that vary strongly across LADs. Enhancers also differ in their sensitivity to LAD chromatin. This work provides a general framework for the systematic understanding of gene regulation by repressive chromatin.\n\nHighlightsO_LITwo promoter transplantation strategies elucidate the regulatory role of LAD chromatin\nC_LIO_LILADs are generally repressive, but also highly heterogeneous\nC_LIO_LILADs can impede both promoter activity and transcription elongation\nC_LIO_LIPromoters vary intrinsically in their sensitivity to LAD repression\nC_LI

genomics↗

bioRxiv2018

Systematic identification of human SNPs affecting regulatory element activity

Most of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help pinpoint SNPs that underlie human traits.

genomics↗