MISREGULATID · Measuring and modeling how misregulation in gene regulatory networks causes intellectual disability
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2014-03-01 → 2018-02-28
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Генните регулаторни мрежи и техните мутации се анализират, за да се разбере как грешното управление на изразяването на гените води до интелектуални увреждания. Това помага да се обясни причината за състоянието при пациенти, при които не са открити стандартни генетични мутации.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Measuring and modeling how misregulation in gene regulatory networks causes intellectual disability
Introduction and aims: Intellectual disability (ID) refers to significant impairments in intellectual functioning and adaptive behavior. ID affects approximately 2% of the population and has a large impact on the individual and society. Currently, mutations in more than 450 genes have been associated with intellectual disability, but the true number of genes involved is expected to be significantly higher. Many disease-causing mutations for ID have been identified in the ~2% of the genome that specifies the protein sequence of ~25,000 genes. The remaining 98% of the genome contains many gene regulatory elements, which are key determinants of the expression (transcription) level of genes. The transcriptional networks defined by gene regulatory elements guide differentiation, establish cell fate and underlie biological pathways. For many ID patients (~40%) no causative mutation in a gene can be identified. A key unresolved question is whether mutations in gene regulatory elements play an important role in ID. The overall aim of the research is to understand how and when perturbation of cooperative binding of transcription factors in gene regulatory elements causes aberrant expression of target genes, and to understand how this aberrant gene expression disrupts transcriptional networks and biological pathways underlying ID and co-morbid disorders of the brain. Results: This project was comprised of a number of subprojects. The results for the subprojects are as follows. 1. We established a previously published protocol to differentiate human induced pluripotent stem cells (hIPSCs) to mature, functional neurons (iNeurons) by overexpression of a single neuronal transcription factor. 2. We characterized these neurons at the epigenetic level using chromatin accessibility profiling (ATAC-Seq), which identifies putative regulatory elements, and gene expression profiling. We have characterized the differences in the chromatin accessibility landscape between iPSCs, characterized the transcriptional networks by transcription factor motif analysis, and related these to changes in gene expression. We have estimated to what extent different classes of regulatory elements contribute to complex neurodevelopmental and psychiatric disorders (proportion of heritability explained and enrichment). 3. We have estimated the contribution of non-coding copy number variation (CNVs), specifically large, rare deletions that only affect regulatory elements, to ID. 4. By analyzing the regulatory networks of skin fibroblasts and iNeurons, we have identified a new set of transcription factors that are able to rapidly induce neuronal morphology and neuronal gene activity when overexpressed in fibroblasts. This provides new insights into the role of these factors in neurodevelopment. Re-integration: The career integration grant has contributed significantly to my career development at the host institution. I will however no longer pursue an academic career at this institution.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Intellectual disability (ID) is a neurodevelopmental disorder with a strong genetic component. For many patients the genetic cause is yet unknown as no protein-damaging mutations can be identified. To accurately predict the risk for ID from a person’s complete DNA sequence, it is essential to know how and when genetic perturbation of a gene regulatory element causes abnormal neurodevelopment. The knowledge and statistical methodology to do so are currently lacking.Recently, the ENCODE and Roadmap Epigenomics projects identified millions of gene regulatory elements across a wide range of tissues. These regulatory elements are small DNA regions where cooperative binding of specific transcription factors (TFs) strongly influences the level of expression of one or more genes, often in a highly tissue-specific manner. However, since only static characterizations are available, it is very difficult to predict how the transcriptional network defined by the regulatory elements responds to genetic perturbations.I will therefore perturb gene regulatory elements underlying ID by knocking-down the expression of established ID transcription factors in neurons. Previous efforts relied on partial or noisy measurements of TF binding. Instead, I will use TF-footprinting to obtain a complete view of how the knock-down perturbs TF-binding in gene regulatory elements. Combining this with gene expression and epigenetic profiling, I will model of how perturbation of cooperative binding in regulatory elements causes misregulation of ID and neurodevelopmental genes. To predict how perturbation of the transcriptional network disrupts biological pathways, I will integrate in my Bayesian network model existing data sets of neuronal morphology, structural brain imaging GWAS, and behavioural studies in model organisms.My research will provide much-needed understanding and methodology to predict the functional consequences of genetic perturbation of gene regulatory elements for ID.
Оригинален текст от CORDIS (на английски).
Участници
- STICHTING RADBOUD UNIVERSITEIT · NijmegenКоординаторНидерландия
Връзки
Данни: CORDIS, © Европейски съюз