Final Report Summary - MISREGULATID (Measuring and modeling how misregulation in gene regulatory networks causes intellectual disability)
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.