H2020Индивидуална стипендия2019–2021

eXcape3D · Functional dissection of X-linked regulatory DNA: unravelling the impact of genome topology on transcriptional regulation

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

Период: 2019-04-01 → 2021-10-01
Финансиране от ЕС: 174 806 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните механизми, при които някои гени от „изключената“ Х-хромозома при жените остават активни, се анализират чрез тяхната 3D структура. Това помага да се разбере развитието на женския организъм и защо жените са по-податливи на определени автоимунни 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

Functional dissection of X-linked regulatory DNA: unravelling the impact of genome topology on transcriptional regulation

The “eXcape3D” project was designed to understand how the genome looks and works by using X Chromosome Inactivation (XCI) as a model system. XCI ensures proper X-linked gene dosage between females (XX) and males (XY), is essential for female development, and results in the transcriptional silencing of almost one entire X chromosome in all cells of every female mammals, including women. Intriguingly, a subset of X-linked genes, the ‘escapees’, resist XCI and remain expressed from both the active (Xa) and inactive (Xi) X chromosomes within the same nucleus. XCI escape is highly relevant for female development and sexual dimorphism. Women born with a single X (XO) are affected by Turner syndrome, but the majority of human XO embryos die in utero. XX women are more susceptible than XY men to autoimmune diseases and this is thought to be due to an excess dose of immunity-related X-linked genes that are prone to be reactivated along the Xi. How escapees resist XCI remains a mystery. According to previous work, the 3D organization of these active loci might be important for their expression. However, whether the structural features of escapees are cause or consequence of their activity is hard to conclude. The objectives of this MSCA project have been to (a) identify DNA regulatory elements that drive escape from XCI, and (b) determine the exact causal relationship between transcriptional activity and chromosome architecture in the context of Xi. The project also aimed to nurture the development of the Fellow into a highly-qualified expert scientist who is fully prepared and motivated to continue her career as a junior group leader in the European Research Area.

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

Цел на проекта

Mammalian genomes are structurally organized into sub-chromosomal self-interacting domains called topologically associating domains (TADs). Functionally, genes embedded within the same TAD appear to be co-regulated by their shared regulatory landscapes, suggesting the tendency of the genome to be divided into discrete regulatory domains. Although disrupting TAD boundaries has been shown to result in aberrant patterns of gene expression, whether TAD organisation is cause or consequence of transcriptional activity remains largely unknown, as well as the regulatory elements that direct TAD formation and long-range chromatin interactions within TADs. This project aims to define the exact functional link between genome topology and transcriptional regulation by exploiting the mammalian dosage compensation mechanism X-Chromosome Inactivation (XCI) as a model system. First, I will identify the combination of regulatory elements that allow a subset of X-linked genes to resist the transcriptional silencing of one entire X chromosome in female cells. Then, I will characterise their functional and structural relevance by combining advanced epigenetic tools for the manipulation of complex regulatory networks with transcriptomic analysis and chromosome conformation capture, an innovative method that allows to define the 3D structure of chromosomes within the nucleus. This project represents a unique opportunity to enhance our understanding of genome topology, providing valuable insights into the roles of the non-coding genome in gene regulation. Considering my personal professional background, and the outstanding level of scientific excellence of the host institution, this project promises a great potential of radically advancing the field and, in addition, will provide the European Research Area with a highly-qualified expert scientist who has the technical and complementary skills to successfully lead a European research team.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания