Low input promoter capture Hi-C method enables to decipher the molecular mechanisms underlying genetically complex diseases
Year: 2022
Type: conference-paper
Abstract: Interactions between promoters and their regulatory elements (e.g., enhancers) are cell-type specific. Moreover, these promoter-enhancer contacts have been shown to be crucial for proper gene expression levels, and their alteration promotes disease [1, 2]. The most widely used experimental methods require tens of millions of cells to obtain the whole high-resolution promoter associations, also called promoter interactome, independently of their activity. This requirement precludes the genome-wide analysis of regulatory promoter interactions in disease-relevant patient samples. This gap of knowledge is particularly problematic for understanding the molecular mechanism underlying inherited risk factors for common human diseases and acquired mutations and epimutations, which all are all highly enriched at regulatory elements. To provide novel insight into global genomic regulatory mechanisms and gene pathways underlying disease pathologies, Javierre et al. implemented promoter capture Hi- C (PCHi-C) method [1]. It allows systematic genome-wide identification of the genomic regions, including distal regulatory regions, in physical proximity with more than 22,000 promoters independently of the activity status of the interacting regions. In addition, due to PCHi-C method relying just on the sequence capture technology, but not in antibody immunoprecipitation as other methods do, it enables the robust compassion between conditions or cell types and the customization to interrogate any specific interactomes (e.g., enhancer interactome or the interactome in which a collection of variants). Applying this method, it has been possible to associate non-coding disease-associated variants to their distal target promoters, identifying hundreds of potential new disease-candidate genes and/or gene pathways. However, PCHi-C relies on the availability of millions of cells, typically from 20 to 50 million per biological replicate, which prohibits the analysis of rare cell populations such as those commonly obtained in clinical settings.
Authors: López-Martí, Paula, Javierre, Biola M, Valencia, Alfonso
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7011339767