H2020Индивидуална стипендия2017–2019

ESEMT · DETERMINING THE FUNCTIONAL CONSEQUENCES OF TRANSCRIPTIONAL ENHANCER ACTIVATION ON ALTERNATIVE SPLICING DURING EMT

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

Период: 2017-10-01 → 2019-09-30
Финансиране от ЕС: 185 076 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Активността на специални регулаторни елементи (енхансери) се проучва при превръщането на епителни клетки в мезенхимни в човешката млечна жлеза. Разбирането на този процес помага да се разбере как се регулира разнообразието от протеини и защо при някои заболявания, като рака, този механизъм се нарушава.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

DETERMINING THE FUNCTIONAL CONSEQUENCES OF TRANSCRIPTIONAL ENHANCER ACTIVATION ON ALTERNATIVE SPLICING DURING EMT

Alternative splicing is a finely regulated process which is essential to create protein diversity within the cell. Dysregulation of this phenomenon can lead to numerous cellular and developmental problems and contribute to emergence of diseases, such as cancer. Understanding the manner in which alternative splicing is regulated during development and in pathologies is therefore of the utmost importance. Recent findings have demonstrated that the regulation of alternative splicing is not only orchestrated by the recruitment of specific proteins (splicing factors) at the messenger-RNA level in a co-transcriptionnal manner but also by other biological phenomena which are more closely linked to epigenetic, such as histone post-translational modifications or long non-coding RNAs. My research project is based on the hypothesis that yet another level of regulation of alternative splicing exists, which is governed by activity modification of transcriptional enhancer elements. Cell-type- and cell-state-specific variation in gene expression patterns are mediated by specialized cis-regulatory elements called enhancers. One of the mechanisms through which enhancers exert their regulatory effect on gene expression is through transcription factor recruitment by chromatin looping. We propose that this differential recruitment of various protein factors and chromatin tridimensional structure remodeling can influence alternative splicing patterns. These enhancer elements would therefore be essential for the establishment and the maintenance of cell-type-specific alternative splicing programs. With this project, I investigate the role of enhancer activity modification in the regulation of alternative splicing during the Epithelial-to-Mesenchymal Transition (EMT) of human mammary cells. The EMT is an important physiological process which has been implicated in early embryogenesis, wound-healing, establishment of tumor metastasis and cancer recurrence. We anticipate that this study will provide results with important ramifications pertaining to the understanding of how cancer-specific alternative splicing programs are established and maintained. Furthermore, this work has the potential to discover novel therapeutic targets that would allow us to reverse the EMT process and therefore reduce tumor metastasis and cancer progression.

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

Цел на проекта

Alternative splicing (AS) is a highly regulated process that is essential for creating the protein diversity required for correct cell-type specification. Misregulation of AS programs can lead to cellular dysfunction, developmental problems and disease, such as cancer. Understanding how alternative splicing is regulated during development and disease is therefore capital.Recent advances in the field have shown that, not only does AS regulation rely on the recruitment of various splicing factors to the pre-mRNA, but other phenomena such as RNA Polymerase II elongation rate, histone post-translational modifications or long non-coding RNAs have been shown to regulate this process.I hypothesize that transcriptional enhancers also play a critical role in the establishment and maintenance of cell-type-specific AS programs. I propose to study the effect of enhancer activation on AS regulation during the epithelial-to-mesenchymal transition (EMT), an important physiological process involved in tumour metastasis and cancer recurrence. Using genome-wide studies, I will map and physically link activated enhancers to intragenic regions of alternatively spliced genes over the course of the EMT in human mammary epithelial cells. I will then employ a candidate-based approach to tease apart the multiple processes through which enhancer activation can regulate splicing patterns, and to discover new enhancer-linked regulators implicated in the AS process.Long-term, this project aims to establish a direct functional link between enhancer activation and alternative splicing during development, with the ultimate ambition of being able to modify AS patterns through the regulation of enhancers. This study will yield results expected to have important implications for the understanding of how cancer-specific splicing programs are established and maintained and have the potential to discover innovative targets to revert EMT and in this way reduce tumour metastasis and cancer progression.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция