The interplay between chromatin structure and transcriptional regulators has an important role in gene regulation throughout development and differentiation. Because the mammary gland develops mostly postnatally and the hormones of puberty and pregnancy tightly regulate its tissue specific gene expression, it makes an excellent model system to study the mechanisms by which chromatin remodeling regulates developmental processes in general. The long-term goal of this research is to determine the role chromatin remodeling plays in the maturation of the mammary gland and regulation of lactation, and identify the pertinent regions in the genome that function as regulatory elements in these processes. Numerous studies have identified the factors involved in transcriptional regulation of mammary specific genes during development. However, the mechanisms by which these genes are regulated globally, at the level of chromatin conformation (epigenetically), to define development and differentiation of the gland have received much less attention. We hypothesize that chromatin remodeling occurs in the mammary gland during development and differentiation, and is an integral part of the regulation of the tissue-specific expression patterns that convey the cellular memory needed for the gland's maturation. A global approach to this problem is now possible with the recent development of ChIP-chip, a new technology combining Chromatin Immuno-precipitation (ChIP) and high-throughput oligonucleotide-tiling arrays (chip). We will use ChIP-chip to establish tissue- and developmental stage-specific patterns of histone modifications (Aim 1a) and RNA-polymerase-II (Aim 1b), in non-mammary, non-locating and lactating mammary gland tissue of the mouse. As milk protein genes are expressed in functionally differentiated mammary epithelial cells, our studies will focus on the genomic domains encompassing these genes, and other developmentally regulated genes. These studies will bring about new knowledge of the factors and pathways regulating mammary gland development and lactation, opening new frontiers in the manipulation of these processes to benefit mother and child. In addition, they will provide a foundation for understanding epigenetic changes that determine differentiation and organogenesis of specific tissues. Public Health Relevance Statement: Milk is the primary source of nutrition for neonates it provides all the essential components for healthy growth and development of newborns of all mammalian species. However, our knowledge of the factors involved in establishing and maintaining lactation is far from complete. In particular the role DNA packaging plays is not well established. In this study we will investigate the DNA packaging in the developing mammary gland at a genome wide scale. These studies will provide a foundation for understanding the mechanisms that determine differentiation and organogenesis of specific tissues.
| Rijnkels, Monique; Kabotyanski, Elena; Montazer-Torbati, Mohamad B et al. (2010) The epigenetic landscape of mammary gland development and functional differentiation. J Mammary Gland Biol Neoplasia 15:85-100 |
