Traditionally eukaryotic genes are considered independently expressed under the
control of their promoters and cis-regulatory domains. However, recent studies in worms,
flies, mice and humans have shown that genes co-habiting a chromatin domain or “genomic
neighborhood” are frequently co-expressed. Often these co-expressed genes neither
constitute part of an operon nor function within the same biological pathway. The
mechanisms underlying the partitioning of the genome into transcriptional genomic
neighborhoods are poorly defined. However, cross-species analyses find that the linkage
among the co-expressed genes of these clusters is significantly conserved and that the
expression patterns of genes within clusters have co-evolved with the clusters. Such
selection could be mediated by chromatin interactions with the nuclear matrix and
long-range remodeling of chromatin structure. In the context of human disease, we propose
that dysregulation of gene expression across genomic neighborhoods will cause highly
pleiotropic diseases. Candidate genomic neighborhood diseases include the nuclear
laminopathies, chromosomal translocations and genomic instability disorders, imprinting
disorders of errant insulator function, syndromes from impaired cohesin complex assembly,
as well as diseases of global covalent histone modifications and DNA methylation. The
alteration of transcriptional genomic neighborhoods provides a model for studying
epigenetic alterations as quantitative traits in complex common human diseases.
Keywords: Gene clusters, genomic neighborhoods, nuclear organization, gene
expression.
