Epigenetic Modifications Unlock the Milk Protein Gene Loci during Mouse Mammary Gland Development and Differentiation

• Published in: PloS one 2013-01, Vol.8 (1), p.e53270-e53270
• Main Authors: Rijnkels, Monique, Freeman-Zadrowski, Courtneay, Hernandez, Joseph, Potluri, Vani, Wang, Liguo, Li, Wei, Lemay, Danielle G, Shioda, Toshi
• Format: Article
• Language: English
• Subjects: Agriculture; Albumins - metabolism; Animals; Biology; Breastfeeding & lactation; Casein; Cell Differentiation; Cellular biology; Chromatin; Chromatin - metabolism; Clusters; dairy protein; Developmental stages; Differentiation; DNA Methylation; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Female; Gene expression; Gene Expression Regulation, Developmental; Gene loci; Gene regulation; Genes; Genetic aspects; Genomes; Goats; Growth factors; Histones - metabolism; Hormones; Lactalbumin; Lactation; Liver; Liver - metabolism; loci; mammary development; Mammary gland; Mammary glands; Mammary Glands, Animal - embryology; Mammary Glands, Animal - growth & development; Medical schools; Medicine; Mice; Milk; Milk proteins; Milk Proteins - genetics; Milk Proteins - metabolism; multigene family; Nutrition research; Pediatrics; Physiological aspects; Pregnancy; Promoter Regions, Genetic; Promoters; Proteins; Puberty; regulator genes; Regulatory sequences; Tissues; transcription (genetics); Transcription factors; Whey; Whey acidic protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053270

Unlike 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 has ceased, while the changes which 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.