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Title: From genes to milk: Genomic organization and epigenetic regulation of the mammary transcriptome

Author
item LEMAY, DANIELLE - University Of California
item POLLARD, KATHERINE - University Of California
item MARTIN, WILLIAM - University Of California
item FREEMAN-ZADROWSKI, COURTNEAY - Children'S Nutrition Research Center (CNRC)
item HERNANDEZ, JOSEPH - Children'S Nutrition Research Center (CNRC)
item KORF, IAN - University Of California
item GERMAN, J. BRUCE - University Of California
item RIJNKELS, MONIQUE - Children'S Nutrition Research Center (CNRC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/8/2013
Publication Date: 9/26/2013
Citation: Lemay, D.G., Pollard, K.S., Martin, W.F., Freeman-Zadrowski, C., Hernandez, J., Korf, I., German, J., Rijnkels, M. 2013. From genes to milk: Genomic organization and epigenetic regulation of the mammary transcriptome. PLoS One. 8(9):e75030.

Interpretive Summary: Breastfeeding has benefits for the short- and long-term health of both infants and mothers, while feeding a growing world population requires the improvement of the quality, efficiency, and sustainability of milk production from dairy cows. To fully understand the biological process of turning on milk production and maintaining milk flow for breast feeding infants or dairy production to feed the world population it is important to understand all aspects of gene regulation. How genes that are located next to each other are expressed at the same time in the same tissue (e.g. in the breast at lactation)—also called gene-neighborhoods—is still not completely understood. Using lactation and the mammary gland as a model system, a new computer program, G-NEST, was used to analyze the genes that are turned on during lactation and their location in the genome, furthermore data sets were generated that identify marks on the genome that reflect whether genes are active or not. Results from these studies indicate that genes are controlled in groups, some genes exist in neighborhoods, and most genes are inactive. We also learned that a small set of genes expressed on their own (not in a neighborhood) distinguishes the lactating mammary gland. This suggests that there could be advantages in grouping genes together that need to be silenced during lactation and that which genes are turned off is just as important as which are turned on. These findings give researchers a better understanding of how milk production is controlled.

Technical 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.