Local and global chromatin interactions are altered by large genomic deletions associated with human brain development

Abstract

BackgroundLarge copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Using Hi-C analysis of long-range chromosome interactions and ChIP-Seq analysis of regulatory histone marks we studied the epigenomic effects of the prominent large deletion CNV on chromosome 22q11.2 and also replicated a subset of the findings for the large deletion CNV on chromosome 1q21.1.\n\nResultsWe found that, in addition to local and global gene expression changes, there are pronounced and multilayered effects on chromatin states, chromosome folding and topological domains of the chromatin, that emanate from the large CNV locus. Regulatory histone marks are altered in the deletion proximal regions, and in opposing directions for activating and repressing marks. There are also significant changes of histone marks elsewhere along chromosome 22q and genome wide. Chromosome interaction patterns are weakened within the deletion boundaries and strengthened between the deletion proximal regions. We detected a change in the manner in which chromosome 22q folds onto itself, namely by increasing the long-range contacts between the telomeric end and the deletion proximal region. Further, the large CNV affects the topological domain that is spanning its genomic region. Finally, there is a widespread and complex effect on chromosome interactions genome-wide, i.e. involving all other autosomes, with some of the effect directly tied to the deletion region on 22q11.2.\n\nConclusionsThese findings suggest novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.