Background Large Copy Number Variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. However, given that these large CNVs each affect many genes directly and an often even larger number of genes indirectly, understanding the molecular mechanisms that connect these loci with the clinical phenotypes is a considerable challenge. Methods Using Hi-C for the genome-wide analysis of long-range chromosome interactions and ChIP-Seq for the analysis of regulatory histone marks we studied the epigenomic effects of the prominent large deletion CNV on chromosome 22q11.2, in a cohort of Lymphoblastoid Cell Lines (LCLs), and also replicated a subset of the findings in LCLs with the common large deletion CNV on chromosome 1q21.1. Results We 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. Discussion These findings outline novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity. Our work demonstrates that there are molecular mechanisms other than the gene expression changes that result from the alteration of the copy number of a given gene, that should be taken into account when studying this problem. Multiple molecular levels of control should be assayed and analyzed in an integrated fashion when studying this essential phenomenon of human genome biology and pathophysiology.