Sanchez-Gaya, V. | bioRxiv Science

bioRxiv2022

POSTRE: a tool to predict the pathological effects of human structural variants

Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long-range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.

bioinformatics↗

bioRxiv2020

Orphan CpG islands boost the regulatory activity of poisedenhancers and dictate the responsiveness of their target genes

ARTICLECpG islands (CGIs) represent a distinctive and widespread genetic feature of vertebrate genomes, being associated with [~]70% of all annotated gene promoters1. CGIs have been proposed to control transcription initiation by conferring nearby promoters with unique chromatin properties2-4. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance and mechanism of action are barely known5-7. Here we show that oCGIs are an essential component of poised enhancers (PEs)8, 9 that boost their long-range regulatory activity and dictate the responsiveness of their target genes. Using a CRISPR/Cas9 knock-in strategy in mESC, we introduced PEs with or without oCGIs within topological associating domains (TADs) harbouring genes with different types of promoters. By evaluating the chromatin, topological and regulatory properties of the engineered PEs, we uncover that, rather than increasing their local activation, oCGIs boost the physical and functional communication between PEs and distally located developmental genes. Furthermore, we demonstrate that developmental genes with CpG rich promoters are particularly responsive to PEs and that such responsiveness depends on the presence of oCGIs. Therefore, our work unveils a novel role for CGIs as genetic determinants of the compatibility between genes and enhancers, thus providing major insights into how developmental gene expression programs are deployed under both physiological and pathological conditions10-12.

genetics↗