H2020Индивидуална стипендия2022–2024

CHROMISE · Identifying Variable Chromatin Modules using single-cell epigenomics

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 203 149 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Променливите хроматинови модули в единични клетки се анализират, за да се разбере как специфични регулаторни зони в ДНК контролират активността на гените. Това помага да се установи защо различните хора имат различна предразположеност към развитие на определени заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Identifying Variable Chromatin Modules using single-cell epigenomics

A thorough understanding of the genetic contribution to complex traits or disease susceptibility is of great biomedical importance, and may allow to prioritize regions for targeted editing of genetic variants that predispose to or are directly causal for onset of disease. However, only a few studies have so far been able to mechanistically disentangle how regulatory variants contribute to variability in human inter-individual disease susceptibility, as most trait-associated variants appear to fall in non-coding, likely regulatory regions of the genome. Classical views postulated that regulatory variation affects the interaction of transcription factors (TFs) with DNA, which locally affects gene expression and chromatin modifications. However, only a small part of inter-individual variable TF binding can be explained by sequence differences in the respective binding sites. Conversely, DNA regions exhibit a high level of local molecular coordination, which are referred to as variable chromatin modules (VCMs) (other names include cis-regulatory domains (CRDs), chromatin nanodomains or microdomains). VCMs comprise coordinated TF binding and modification of histones in confined genomic locations, which collectively define the activity of the entire locus, i.e. the whole VCM. Within these VCMs, genetic variation can impact chromatin accessibility independent of gene expression, and genetic changes in only certain regulatory elements (REs) can control the activity profile of all other molecular phenotypes. Here we have benchmarked and outlined the best practices to infer VCMs from high-throughput epigenomics data. We further show that single-cell epigenomics (via assay for transposase-accessible chromatin with sequencing (ATAC-seq)) may provide a new means to map VCMs from limited input material. Finally, we provide evidence that VCMs are dynamic during cell state changes, even when the underlying regulatory elements may not change in their epigenetic profile.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Most common disease-associated genetic variants are thought to fall into gene regulatory regions, where they affect the interaction between transcription factors (TFs) and DNA and induce transcriptional changes. To understand the extent of, and the mechanisms underlying variation in binding of TFs to DNA, genome-wide TF and chromatin state profiling studies were performed which revealed that non-coding variants frequently mediate coordinated changes in TF binding and chromatin mark enrichment over regions that span more than 100 kb. These regions were termed “variable chromatin modules” (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. However, little is known about the formation, function, or plasticity of VCMs. This is because vast amounts of epigenomics data have so far been required for identifying VCMs, making their identification costly, labour-intensive, and only applicable to easy-to-culture cell types. Recent work has demonstrated the value of ATAC-seq for defining regulatory element hierarchies that conceptually resemble VCMs. Here, I propose to extend these principles by developing an experimental and computational workflow for VCM identification using single-cell ATAC-seq. This will allow sample multiplexing for sequencing followed by genotype-based demultiplexing, thereby increasing throughput, minimizing sample input, and mitigating variation between samples (Aim 1). I will apply this workflow to study VCM plasticity during human mesenchymal stromal cell differentiation (Aim 2). The resulting data will be used to identify VCM-linked metabolic disease-relevant genetic variants, whose role in VCM formation will be validated using CRISPR-Cas9 (Aim 3).

Оригинален текст от CORDIS (на английски).

Участници

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE · LausanneКоординаторШвейцария