CTCF mediated genome architecture regulates the dosage of mitotically stable mono-allelic expression of autosomal genes

Abstract

Mammalian genomes exhibit widespread mono-allelic expression of autosomal genes. However, the mechanistic insight that allows specific expression of one allele remains enigmatic. Here, we present evidence that the linear and the three dimensional architectures of the genome ascribe the appropriate framework that guides the mono-allelic expression of genes. We show that: 1) mono-allelically expressed genes are assorted into genomic domains that are insulated from domains of bi-allelically expressed genes through CTCF mediated chromatin loops; 2) evolutionary and cell-type specific gain and loss of mono-allelic expression coincide respectively with the gain and loss of chromatin insulator sites; 3) dosage of mono- allelically expressed genes is more sensitive to loss of chromatin insulationn associated with CTCF depletion as compared to bi-allelically expressed genes; 4) distinct susceptibility of mono- and bi-allelically expressed genes to CTCF depletion can be attributed to distinct functional roles of CTCF around these genes. Altogether, our observations highlight a general topological framework for the mono-allelic expression of genes, wherein the alleles are insulated from the spatial interference of chromatin and transcriptional states from neighbouring bi-allelic domains via CTCF mediated chromatin loops. The study also suggests that the three-dimensional genome organization might have evolved under the constraint to mitigate the fluctuations in the dosage of mono-allelically expressed genes, which otherwise are dosage sensitive.