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Reorganization of inter-chromosomal interactions in the 2q37-deletion syndrome

Journal Contribution - Journal Article

Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter-chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and interactions between the three chromosomal territories with a tissue-specific interaction bias at certain loci. These inter-chromosomal interactions were confirmed by Hi-C. Interestingly, the disease-related HDAC4 deletion resulted in displaced inter-chromosomal arrangements and altered interactions between the deletion-affected chromosome 2 and chromosome 12 and/or 17 in 2q37-deletion syndrome patients. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis.

Journal: EMBO Journal
ISSN: 0261-4189
Issue: 15
Volume: 37
Publication year:2018
Keywords:Cell Nucleus/genetics, Chromosome Deletion, Chromosomes, Human, Pair 12/genetics, Chromosomes, Human, Pair 17/genetics, Chromosomes, Human, Pair 2/genetics, Gene Deletion, Histone Deacetylases/genetics, Humans, In Situ Hybridization, Fluorescence, Interphase/genetics, Mesenchymal Stem Cells/cytology, Repressor Proteins/genetics, Translocation, Genetic/genetics