Spatial clustering and common regulatory elements correlate with coordinated gene expression

TL;DR

This study reveals that genes with similar expression patterns tend to be spatially clustered in the genome, suggesting a link between 3D chromosome structure and coordinated gene regulation in eukaryotic cells.

Contribution

It introduces a combined analysis of gene expression, epigenomic, and 3D genome data to show spatial clustering of co-expressed genes across large genomic distances.

Findings

Genes with similar expression profiles are spatially close in the nucleus.

Spatial clustering occurs despite large genomic distances between genes.

Similar patterns are observed in mouse nervous system development.

Abstract

Many cellular responses to surrounding cues require temporally concerted transcriptional regulation of multiple genes. In prokaryotic cells, a single-input-module motif with one transcription factor regulating multiple target genes can generate coordinated gene expression. In eukaryotic cells, transcriptional activity of a gene is affected by not only transcription factors but also the epigenetic modifications and three-dimensional chromosome structure of the gene. To examine how local gene environment and transcription factor regulation are coupled, we performed a combined analysis of time-course RNA-seq data of TGF-\b{eta} treated MCF10A cells and related epigenomic and Hi-C data. Using Dynamic Regulatory Events Miner (DREM), we clustered differentially expressed genes based on gene expression profiles and associated transcription factors. Genes in each class have similar temporal gene expression patterns and share common transcription factors. Next, we defined a set of linear and radial distribution functions, as used in statistical physics, to measure the distributions of genes within a class both spatially and linearly along the genomic sequence. Remarkably, genes within the same class despite sometimes being separated by tens of million bases (Mb) along genomic sequence show a significantly higher tendency to be spatially close despite sometimes being separated by tens of Mb along the genomic sequence than those belonging to different classes do. Analyses extended to the process of mouse nervous system development arrived at similar conclusions. Future studies will be able to test whether this spatial organization of chromosomes contributes to concerted gene expression.