Human milk has been shown to provide significant health benefits to infants. However the impact of human milk feeding for infants depends in part on the functional capacity of the mother's mammary gland. Both milk production capacity and expression of specific milk components that confer health benefits vary between women. This variation impacts the mother's ability to breastfeed according to recommendations and the value of her breast milk to the recipient infant. In order to address this critical variability between women, it is necessary to understand the underlying mechanisms through which variations in mammary gland function arise. The extent to which these variations are influenced by epigenetic regulation during development is unknown. Moreover, mechanisms of epigenetic control of gene expression in the mammary gland are not characterized. This proposal will address basic mechanisms of epigenetic control of gene expression within the context of mammary biology. The model has been chosen for two reasons: first because performing the work in mammary tissue will enable rapid application of findings to clinical lactation questions. Second, use of this model provides a relatively easy system within which to observe the targeted phenomena. The long-term goal of this research is to determine the role epigenetics and chromatin remodeling play in the functional development of the mammary gland and lactation, and to identify the pertinent regions in the genome that function as regulatory elements. The specific hypothesis is that developmental- and tissue-specific gene expression is regulated by the concerted action of proximal promoters, distal regulatory elements and the chromatin in which they reside. This is based on results in the literature demonstrating that 1) the concerted action of distal and proximal transcriptional regulators and chromatin play a crucial role in gene regulation during development and differentiation,2) these elements are characterized by DNaseI hypersensitivity, and 3) our own preliminary data, which show tissue- and developmental stage-specific DNaseI hypersensitivity, histone modification and DNA methylation of promoters, distal regulatory elements and evolutionary conserved regions of unknown function which correlates with expression.
The specific aim of this proposal is to determine mammary gland tissue- and developmental stage specific DNaseI hypersensitive sites (HS) in large genomic domains encompassing mammary gland developmentally regulated genes. We will use DNase-chip, a new array approach that combines DNaseI HS mapping with DNA oligo tiling microarrays, to compare lactating mammary gland tissue of the mouse with non-lactating and non-mammary tissue for genomic regions harboring the milk protein genes and other developmentally regulated genes. This study will contribute to our knowledge of the factors and pathways regulating mammary gland development and lactation. Milk is the primary source of nutrition for neonates it provides all the essential components for healthy growth and development of newborns. However, our knowledge of the factors involved in establishing and maintaining lactation is far from complete, in particular how the packaging of the DNA contributes to the development of the mammary gland and the location of all the regulatory DNA elements involved. In this study we will investigate these aspects in developing mammary gland tissue at a genome wide scale. These studies will provide a foundation for understanding the mechanisms that determine the functional capacity of the mother's gland. ? ? ?
| 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 |
