H2020Индивидуална стипендия2017–2018

4DGenomeReg · Predictive modelling of 3D genome topology during progressive stages of embryonic development

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

Период: 2017-01-01 → 2018-12-31
Финансиране от ЕС: 171 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

Тритеизмерната структура на генома при плодови мухи се проследява по време на ембрионалното развитие, за да се види как отдалечени регулаторни елементи достигат до целевите гени. Разбирането на тези механизми помага да се обясни появата на рак и някои вродени нарушения.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Predictive modelling of 3D genome topology during progressive stages of embryonic development

Transcriptional regulation is an extremely complex process that allows for appropriate readout of genetic information in every living organism. This process is particularly important during development and disease, and controlled by intricate mechanisms of DNA regulatory elements. These regulatory elements, including gene promoters and distal enhancers, compile regulatory signals received through transcription factor binding. The three-dimensional architecture of the genome brings enhancers, often located at large linear distance along the genome, into spatial proximity to the target genes. On a larger scale, the genome is partitioned into Topologically Associated Domains (TADs), characterized by having internal contacts more frequent than contacts to the outside regions. TAD boundaries are thought to insulate regulatory environments between adjacent TADs, preventing gene promoters from being inadvertently activated by enhancers located in other TADs. Several studies showed that disruption of a TAD boundary could affect expression of genes on the other side of the boundary through enhancer hijacking. This is also the case for naturally occurring structural variants that disrupt TAD boundaries, and this mechanism has been shown to have a role in driving certain developmental disorders and cancers. This project used chromosome conformation capture techniques, Hi-C and Capture-C, to measure chromatin topology at a genome-wide scale in the context of embryonic development of Drosophila melanogaster. We performed Hi-C experiments during multiple stages of development spanning the entire embryonic timespan to determine if the chromatin interaction landscape observed during the early stages of development is maintained to the end of embryogenesis. For this purpose, we identified topologically associated domains (TADs) and annotated long-range looping interactions. To investigate the relationship between genome topology and gene expression, we utilized highly rearranged balancer chromosomes, which contained eight large nested inversions, thousands of smaller structural variants, and hundreds of thousands of single nucleotide variants. We then assessed the impact of these genomic rearrangements on genome topology and gene expression in cis, using a heterozygous cross (balancer over wild-type), which minimizes the contribution of trans effects. For this purpose, we performed allele-specific Hi-C and RNA-seq experiments on F1 embryos.

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

Цел на проекта

The mechanisms that regulate genome activation and gene expression occur within a complex three-dimensional (3D) architecture, that helps bring functional regulatory elements into spatial proximity. Although observed at individual loci, the general principles and dynamics of enhancer-promoter interactions remain very poorly understood. The proposed project will use chromosome conformation capture, Hi-C, to measure 3D chromatin interactions at a genome-wide scale across different stages of embryogenesis.The project will build on the Furlong lab’s recent findings in genome topology. First, it will look at changes in chromosome conformation during the entire developmental time-span to determine if the stability of interactions observed during the early stages holds true to the end of embryogenesis. It will also compare high-resolution interaction frequencies in two different cells types (mesodermal and neuronal) during different stages of development. The project will consider the entire spectrum of possible interactions, as opposed to a narrow set of enhancers, and thereby yield the first high-resolution view of the overall topology of the Drosophila genome as it develops and the general ‘search-space’ of developmental enhancers. Second, the results will identify constitutive and dynamic chromatin interactions, revealing the extent to which enhancer-promoter interactions change between cell types as they transition from a multipotent state to a terminally differentiated tissue. Third, these data will be used to make an integrative predictive model of chromatin loop formation, which should yield mechanistic insights into how chromatin contacts are formed and predict their dynamic or constitutive behaviour.Given that the general principles underlying genomic architecture are deeply conserved, the project should not only help to explain regulatory principles underlying Drosophila development, but also greatly enhance our understanding of general chromatin organization.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания