ROQ-WACh · Identification and Characterization of Cis-Regulatory Module Dysfunction in Rett Syndrome with ROQ-WACh
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2016-03-01 → 2018-02-28
- Финансиране от ЕС
- 158 122 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Генните регулатори (CRMs) в невроните се анализират чрез новия метод FIRE-WACh, за да се разбере как работят при синдрома на Рет. Това помага да се изясни как грешки в тяхната функция водят до развитие на аутизъм и рак.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Identification and Characterization of Cis-Regulatory ModuleDysfunction in Rett Syndrome with ROQ-WACh
Proper gene expression is essential for the execution of cellular function. Disruption of this process results in pathologies such as autism and cancer. These diseases have an enormous impact on society both economically as well as for the quality of life of its members. As such this proposal aimed to address an important issue that will impact a large portion of society. The regulation of gene expression is achieved on the molecular level by the coordinated action of genomic elements termed cis-regulatory modules (CRMs). Recent genomics studies suggest each gene has ~ 20 CRMs (e.g. promoters and enhancers) to establish precise transcription patterns. CRMs recruit transcription factors and RNA polymerase to a gene’s transcription start site1 in a sequence specific manner and may be sensitive to epigenetic modifications such as DNA methylation. DNA methylation is an important epigenetic modification whose dysregulation plays an important role in the onset of diseases such as cancer and autism. Specifically, for example, mutations in the MeCP2 gene, which encodes protein that binds methylated DNA and regulates gene expression in neurons, results an Autism Spectrum Disorder termed Rett Syndrome (RTT). While thought to modulate CRM activity as a repressor, MeCP2’s function remains ambiguous and would benefit from a functional genomics characterization. The purpose of this Marie Sklodowska-Curie (MSC) action proposal was three fold. My prior studies led to the development of a novel method to identify active CRMS called FIREWACh (functional identification of regulatory elements within accessible chromatin) and the first goal of this study was to utilize FIRE-WACh to identify active CRMS in neuronal cells. The second aim of this study was to further develop the methodology to adapt FIREWACh into a quantitative approach termed ROQ-WACh(regulatory output quantification within accessible chromatin) so as to detect changes in the level of activity of CRMs. Lastly, I hoped to develop an in-vitro model of RTT using stem cell derived neurons to probe changes in CRM activity with ROQ-WACh. As with all studies, serious challenges arose in the execution of these aims, but those obstacles were informative and have led to a better understanding of both cis-regulatory modules and the etiology of RTT. The work performed under this action resulted in the discovery of neuronal specific CRMs as well as the development of an in vitro model system of RTT. Importantly this action allowed the transfer of knowledge both to the host lab as well as to the public throught the creation of a science outreach program.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Precise regulation of gene expression is achieved through the coordinated action of genomic cis-regulatory modules (CRMs). The identification of CRMs has long been a goal of functional genomics as CRM dysregulation can have devastating consequences for health and development such as autism. For example, mutations in the MeCP2 gene, which encodes protein that binds methylated DNA and regulates gene expression in neurons, results an Autism Spectrum Disorder termed Rett Syndrome. While thought to modulate CRM activity as a repressor, MeCP2’s function remains ambiguous and would benefit from a functional genomics characterization. To identify CRMs I recently developed a novel approach called FIREWACh. Here, I propose to utilize FIREWACh first to identify active CRMs within a homogenous population of neurons, identifying genomic loci of CRMs whose function may be compromised by MeCP2 mutations. I will adapt FIREWACh to allow the quantification of CRM output in a new method I propose to call ROQ-WACh (regulatory output quantification within accessible chromatin) by addition of barcodes to reporter mRNAs. This will allow high-throughput readout of CRM activity globally in vivo and will be broadly applicable to many biological fields. Lastly, I aim to combine the above approaches to quantify the changes in CRM output in response to pathological mutations in MeCP2. This Marie Sklodowska-Curie Action will allow me (the Experienced Researcher, Matthew Murtha) mobility to Spain to join the laboratory of Dr. Manel Esteller (Host Supervisor), renowned epigeneticist and expert in DNA-methylation biology to perform the research. Together the approaches and data generated by this MSCA action will provide key insights into the relationship between methylated DNA, precise control of gene expression, and high-order phenotypes such as cognitive behaviors.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE · L'Hospitalet De LlobregatКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз