H2020Индивидуална стипендия2016–2020

NGECA · REGULATION OF NEURONAL GENE EXPRESSION THROUGH CHROMOSOME ARCHITECTURE

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

Период: 2016-11-01 → 2020-06-01
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF-EF-RI

Линиите свързват координатора с партньорите.

Накратко на български

Разположението на гените в 3D пространството на ядрото влияе върху работата им, като например генът Bdnf се премества, за да активира растежа на дендритите. Разбирането на тези процеси помага да се разберат причините за възникването на неврологични разстройства.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

REGULATION OF NEURONAL GENE EXPRESSION THROUGH CHROMOSOME ARCHITECTURE

Development of the brain is a complex and highly ordered process, requiring activation and silencing of specific repertoires of genes. There are many levels of regulation to ensure these changes occur in a coordinated and timely manner; disruption of appropriate gene expression can lead to neurological disorders. One aspect of gene regulation that has not been fully explored in the brain is the impact of gene location within the 3D nucleus. It is known that the nuclear periphery is generally repressive, and that some genes move to the interior during activation. Moreover, separated genomic regions can come together in 3D space through looping, enabling co-regulation. This can be of different genes in the same biological pathway, or of genes with enhancers that increase their transcription. The objectives of my project were to explore the role of genome looping and gene movement within the nucleus on neuronal gene expression and function. I began with a panel of genes that are important for brain development and assessed the genomic regions they interact with. This led me to identify the first enhancer for Bdnf, which encodes a neurotrophin that is critical for neuronal differentiation and synaptic plasticity. The interacting region bears many hallmarks of enhancers, including chromatin accessibility, histone modifications and transcription factor binding. Importantly, I have demonstrated that the putative enhancer is transcribed, and that inhibition of the region prevents Bdnf functioning in dendritic growth. Furthermore, I have found that Bdnf moves away from the nuclear periphery during its developmental activation, and that the chromosome region in which it resides undergoes topological restructuring. Mis-regulation of Bdnf expression is implicated in a variety of neurological disorders, including those arising during development, and in neurodegeneration. Therefore, understanding its many-faceted regulation is important for understanding and treating disease.

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

Цел на проекта

A remarkable feature of the brain is its ability to adapt to changing environmental conditions. Modulation of synaptic strength and neuronal circuitry underlies experience-dependent learning, and requires widespread changes in gene expression. Following neuronal depolarisation, intracellular signalling results in rapid induction of many activity-regulated genes (ARGs). There are numerous interconnected levels of gene regulation; one critical aspect relates to the three-dimensional conformation of chromosomes within the nucleus. Looping of genes to regulatory regions and to other genes is required for transcriptional activation in other cell types, but remains largely unexplored in neurons. In this proposal, I will investigate how the genome architecture changes during neuronal depolarisation, and how this influences activity-induced transcription and neuronal plasticity. I will first map the genomic interactions of ARGs in neurons before and after depolarisation. This experimental approach will allow identification of enhancer-promoter loops and multi-gene complexes in an unbiased manner. Single-cell imaging studies will be performed to quantify the frequency of interactions across individual neurons. I will use super-resolution microscopy to simultaneously analyse multiple loci with high precision, providing unprecedented detail of gene interactions in response to neuronal activity. Finally, I will use genome editing to disrupt specific chromosomal contacts and evaluate the transcriptional induction of associated genes. I will assess whether loss of genomic contacts affects dendritic growth, a process associated with neuronal plasticity and dependent on ARG induction, to understand the biological implications of chromosome looping. The aim of this project is to discover novel molecular mechanisms that govern transcription during neuronal activation, which is critical in experience-dependent learning.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITY COLLEGE LONDON · LondonКоординаторОбединеното кралство