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Title: Epigenetic modifications unlock the milk protein gene loci during mouse mammary gland development and differentiation

Author
item RIJNKELS, MONIQUE - Children'S Nutrition Research Center (CNRC)
item FREEMAN-ZADROWSKI, COURTNEAY - Children'S Nutrition Research Center (CNRC)
item HERNANDEZ, JOSEPH - Children'S Nutrition Research Center (CNRC)
item POTLURI, VANI - Children'S Nutrition Research Center (CNRC)
item WANG, LIGUO - Baylor College Of Medicine
item LI, WEI - Baylor College Of Medicine
item LEMAY, DANIELLE - University Of California

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/27/2012
Publication Date: 1/2/2013
Citation: Rijnkels, M., Freeman-Zadrowski, C., Hernandez, J., Potluri, V., Wang, L., Li, W., Lemay, D.G. 2013. Epigenetic modifications unlock the milk protein gene loci during mouse mammary gland development and differentiation. PLoS One. 8(1)e53270:1-16.

Interpretive Summary: The mammary gland develops mostly after birth. The roles of hormones and other growth factors in the development of the gland have been well studied but it is less understood how the genes encoding the milk protein genes are regulated to be expressed only in the mammary gland and only during lactation. We studied the role of the packaging/organization of DNA in the cell in this specific regulation. We show that there is a specific organization of the DNA in the genome around milk protein encoding genes in the mammary gland compared to the liver and that this organization changes to a more open organization that is favorable for gene expression when the gland becomes ready to produce milk.

Technical Abstract: Unlike with other tissues, development and differentiation of the mammary gland occur mostly after birth. The roles of systemic hormones and local growth factors important for this development and functional differentiation are well-studied. In other tissues, it has been shown that chromatin organization plays a key role in transcriptional regulation and underlies epigenetic regulation during development and differentiation. However, the role of chromatin organization in mammary gland development and differentiation is less well-defined. Here, we have studied the changes in chromatin organization at the milk protein gene loci (casein, whey acidic protein, and others) in the mouse mammary gland before and after functional differentiation. Distal regulatory elements within the casein gene cluster and whey acidic protein gene region have an open chromatin organization after pubertal development, while proximal promoters only gain open-chromatin marks during pregnancy in conjunction with the major induction of their expression. In contrast, other milk protein genes, such as alpha-lactalbumin, already have an open chromatin organization in the mature virgin gland. Changes in chromatin organization in the casein gene cluster region that are present after puberty persisted after lactation ceased, while the changes that occurred during pregnancy at the gene promoters were not maintained. In general, mammary gland expressed genes and their regulatory elements exhibit developmental stage- and tissue-specific chromatin organization. A progressive gain of epigenetic marks indicative of open/active chromatin on genes marking functional differentiation accompanies the development of the mammary gland. These results support a model in which a chromatin organization is established during pubertal development that is then poised to respond to the systemic hormonal signals of pregnancy and lactation to achieve the full functional capacity of the mammary gland.