  Genome-wide analysis of distributions of densities of long-range interactions
of human chromosomes with each other, nucleoli, nuclear lamina, and binding
sites of chromatin state regulatory proteins, CTCF and STAT1, identifies
non-random highly correlated patterns of density distributions along the
chromosome length for all these features. Marked co-enrichments and clustering
of all these interactions are detected at discrete genomic regions on selected
chromosomes, which are located within pericentromeric heterochromatin and
designated Centromeric Regions of Interphase Chromatin Homing (CENTRICH).
CENTRICH manifest 199-716-fold higher density of inter-chromosomal binding
sites compared to genome-wide or chromosomal averages (p =
2.10E-101-1.08E-292). Sequence alignment analysis shows that CENTRICH represent
unique DNA sequences of 3.9 to 22.4 Kb in size which are: 1) associated with
nucleolus; 2) exhibit highly diverse set of DNA-bound chromatin state
regulators, including marked enrichment of CTCF and STAT1 binding sites; 3)
bind multiple intergenic disease-associated genomic loci (IDAGL) with
documented long-range enhancer activities and established links to increased
risk of developing epithelial malignancies and other common human disorders.
Using distances of SNP loci homing sites within genomic coordinates of CENTRICH
as a proxy of likelihood of disease-linked SNP loci binding to CENTRICH, we
demonstrate statistically significant correlations between the probability of
SNP loci binding to CENTRICH and GWAS-defined odds ratios of increased risk of
a disease for cancer, coronary artery disease, and type 2 diabetes. Our
analysis suggests that centromeric sequences and pericentromeric
heterochromatin may play an important role in human cells beyond the critical
functions in chromosome segregation.
