HEИндивидуална стипендия2022–2024

3-D Cardioid · Decoding enhancer usage and gene expression of human heart development in 3-D cardioids

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

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 189 687 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Развитието на човешкото сърце се проучва чрез 3D органоиди, за да се види как генетични мутации влияят върху растежа им. Това помага за по-доброто разбиране на причините за вродените сърдечни дефекти и търсенето на начини за тяхното предотвратяване или лечение.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Decoding enhancer usage and gene expression of human heart development in 3-D cardioids

The heart is the first organ to form and function during embryo development, and understanding how it develops is crucial for addressing birth defects. While animal models have provided valuable insights, they don't fully represent human heart development. Recent advances in stem cell technology and 3D organoid models offer a technological leap to study human heart development in the lab. However, current organoid models have limitations, such as producing immature cells or favoring certain cell types over others. To overcome these challenges, advanced techniques measuring single-cell gene expression and chromatin accessibility sequencing can help identify the genes and regulatory elements involved in heart development with great detail, potentially leading to a better understanding of how heart defects occurs during early heart development. The primary objectives of the project were 1) to catalog dynamic changes in gene activity and regulation throughout the development of heart organoids, 2) to assess the extent to which these laboratory-grown organoids mirror the development of real human heart development 3) to investigate how genetic mutations associated with heart defects influence the developmental trajectories of these organoids. Together, the results of this research will significantly advance our understanding of heart development and may lead to novel approaches for preventing or treating congenital heart disorders.

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

Цел на проекта

The early steps of heart formation during embryogenesis require precise spatiotemporal coordination between different heart progenitors to join together to form a beating heart tube. This complex biological process is regulated through an evolutionary conserved gene regulatory network (GRN) of transcription factors and cis-regulatory elements that integrate inductive signals from surrounding tissues to ensure correct heart development. Yet, how this process is controlled during heart development, and how mutations impacting the cardiac GRN leads to cardiomyopathies, remains unclear. There is currently little or no information about human heart enhancers during these early stages of heart development. Here, we will first determine the dynamic changes in the usage of regulatory elements and gene expression that accompanies human heart development using heart organoids (cardioids) derived from human induced pluripotent stem cells. To uncover the underlying GRN, we will apply scRNA-seq and scATAC-seq to 3-D cardioids at different stages of development, which will allow us to map enhancer usage during cell fate transitions in human heart development for the first time in vitro. Moreover, we will study how developmental trajectories are altered in disease-relevant mutant 3-D cardioids models. Last, we will study how perturbations of transcription factors influence enhancer function and gene expression by fine-tuning the nuclear level of key regulators using an optogenetic tool developed by the Furlong lab, which is extremely dynamic providing very precise temporal resolution, in the order of minutes. The functional impact of these perturbations will be assessed by scRNA-seq and scATAC-seq to identify the transcription factors’ regulatory mechanisms. Together, these findings will advance our understanding of gene regulation during cardiogenesis by identifying fundamental principles of enhancer usage and transcriptional changes during normal and diseased heart development.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания