Exploring NHCCs toward understanding their contribution to gene regulation and genome organization in health and disease. (A) SNP-CLING enables the study of allele-specific locus positioning and spatiotemporal dynamics in living cells (depicted example: mESC with exemplified time-lapse imaging of a maternal and paternal allele and their distances to the nucleolus). (B) Left: Maternal and paternal alleles of the interphase genome are in physical proximity and intermingle to control tissue-specific gene regulation in the 3D space of the nucleus. LncRNAs, proteins (chromatin modifiers, transcription factors, etc.), biophysical properties of the chromatin, genome organization, and stochastics cooperate to contribute to variable, but specific, biological processes. Right: Structural (i.e., deletions, translocations, etc.) and numerical chromosomal aberrations (e.g., trisomies) can disrupt and reorganize the intricate network of NHCCs. These aberrations cause altered transcriptional programs, repositioning of genomic loci, and reorganization of tissue-specific gene regulation that can influence genetic and developmental processes. They comprise a variable layer of genome organization and are often associated with pathogenic pathways and disease.