Xi Chen, Ph.D.Research Scientist, Genomics, CCB, Flatiron Institute
Title: Tissue-specific enhancer functional networks for associating distal regulatory regions to disease
Abstract: Understanding disease-associated dysregulation of enhancers has the potential to reveal pathogenic signals, yet systematic study of tissue-specific function of enhancers and their disease associations is a major open challenge. We present an integrative framework, FENRIR, that integrates thousands of transcription factor binding (ChIP-seq) and chromatin interaction experiments (ChIA-PET) with functional networks of genes to infer tissue-specific functional relationships between enhancers for 140 diverse human tissues and cell types. FENRIR provides a novel regulatory-region-centric approach to systematically identify disease-associated enhancers. We focused on the brain-specific network and demonstrated its power to accurately prioritize enhancers associated with several complex neurological diseases, including autism spectrum disorder (ASD), Alzheimer’s disease, Parkinson’s disease and Schizophrenia. Our top prioritized ASD-associated enhancers showed a significant proband-specific de novo mutation enrichment, indicating pathogenic signal. Furthermore, we experimentally validated transcriptional regulatory activities of three enhancers not previously reported with ASD and demonstrated their differential regulatory potential between ASD proband and sibling alleles. Thus, FENRIR is an accurate and effective framework for the study of tissue-specific enhancers and their role in disease. FENRIR can be accessed at fenrir.flatironinstitute.org/.