Abstract
Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival.
Highlights
Bacterial operons exemplify how a gene’s expression is affected by proximity to neighboring genes
To verify whether relative gene position has any influence on co-expression of genes in the mammary gland, we computed the mean pairwise gene expression correlation (Spearman’s) for genes within a given genomic interval
To determine whether gene neighborhoods were consistent with chromatin domain boundaries, we reviewed all possible adjacent gene pairs for their neighborhood (TNS) and chromatin domain scores (DS)
Summary
Bacterial operons exemplify how a gene’s expression is affected by proximity to neighboring genes. When a gene translocates from one genomic position to another, the expression of that gene often changes. The alteration of a gene’s neighborhood over evolutionary time can alter gene expression [1,2]. Essential genes – those required for an organism’s survival – are more resistant to altered gene expression that results from genomic rearrangement [1]. Neighborhoods of mammalian co-expressed genes often form through tandem duplications and are preferentially maintained when they are composed of functionally linked, non-essential genes [3]. The mechanisms by which neighboring genes are co-expressed in eukaryotic genomes are incompletely understood
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