H2020Индивидуална стипендия2018–2020

3Dcis · 3D Organization of Functionally Conserved Cis-Regulatory Elements

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

Период: 2018-04-01 → 2020-03-31
Финансиране от ЕС: 158 122 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

3D структурата на хроматина и работата на енхансерите (генни превключватели) се анализират при зебрата и жабата. Това помага да се разбере как се поддържат еднаквите модели на развитие при различните гръбначни животни, въпреки разликите в техните генетични последователности.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

3D Organization of Functionally Conserved Cis-Regulatory Elements

Precise gene expression during embryonic development is crucial to generate the numerous cell types and tissues that build the animal body plan. This patterning is driven by developmental genes that are often expressed in a complex and conserved fashion. Gene expression patterns are instructed by regulatory sequences in the genome, the so-called enhancers. Enhancers act as switches in the genome that can modulate gene expression levels and turn a gene on or off. Given this important function for gene regulation, it is surprising that enhancers are often not conserved at the sequence level and act rather as seemingly variable entities during genome evolution. However, the mechanisms that allow this regulatory plasticity during evolution, but also maintenance of conserved genes expression during development are not well understood. Enhancers together with their target genes are spatially organized into conserved 3D chromatin structures, suggesting that spatial conformation within the nucleus is the missing link between less conserved enhancers and conserved target gene expression during animal development. This project aims to understand the functional relationship between enhancers, conserved gene expression patterns and 3D chromatin structure during vertebrate development and evolution. As sequence conservation of enhancers is extremely limited, we applied innovative approaches to identify and systematically compare the functional response of enhancers and gene expression across different animal lineages. We identified functionally conserved enhancers and their target genes in the distantly related vertebrate model organisms, zebrafish (Danio rerio) and the western clawed frog (Xenopus tropicalis). Assessing the underlying 3D chromatin architecture, we deciphered the chromatin structures at orthologous genomic regions and enriched our understanding of how the cis-regulatory information of enhancers and genome structure translate into function. Although enhancers are not constrained by sequence conservation, they are constrained by conserved structural properties in the nucleus. Our data pave the way towards a deeper understanding of cis-regulatory mechanisms during development and evolution but also towards a better evaluation of regulatory mutations that are frequently detected in human congenital disease and cancer.

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

Цел на проекта

Embryonic development requires precise spatio-temporal gene expression generating numerous cell types that build the animal body plan. Cell-fate specification and patterning are driven by developmental genes that are often expressed in complex and conserved fashion. Gene expression is precisely modulated by gene regulatory networks (GRNs) constructed through the integration of signalling pathways acting at cis-regulatory elements (CREs). While signalling pathways and GRNs are evolutionary constrained, CREs are poorly conserved at the sequence level, posing the question which cis-regulatory mechanisms facilitate coordinated and conserved gene expression patterns during animal development and evolution. CREs and their target genes are spatially restricted into conserved 3D chromatin structures suggesting a possible link between the less conserved CREs and highly conserved gene expression patterns.In this proposal, I aim to identify CREs that differentially respond to signalling cascades. Novel approaches, such as HiChIP and capture Hi-C, will be applied to decipher the chromatin structure of the associated CREs and their target genes. The application of this approach in two distantly related vertebrate model organisms will allow me to gain insight into genome-wide evolutionary conserved nodes of GRNs controlled by these pathways. Furthermore, detailed analysis of chromatin structures induced by activation or inhibition of signaling cascades will further contribute to understanding of co-dependency and complementarity of genome architecture, cis-regulatory information, and signalling pathways. 3Dcis research will shed light on the mechanisms driving conserved gene expression patterns and common body structures, but also the constraints that different animal lineages have faced during their evolutionary path. Finally, the results will make ground breaking advances in our understanding of how cis-regulatory information and structure of our genome translate into function

Оригинален текст от CORDIS (на английски).

Участници

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MadridКоординаторИспания