Venezia by PVII

Monique Rijnkels Ph.D.

Assistant Professor, Department of Pediatrics
Baylor College of Medicine
rijnkel@bcm.tmc.edu

Ph.D. - Leiden University , Leiden , The Netherlands
Postdoctoral - Baylor College of medicine, Houston

Chromatin Remodeling In Mammary Gland Development

Insight in the development and functional differentiation of the mammary gland is essential if we are to understand the mechanisms regulating lactation. Milk is the primary source of nutrition for neonates and has been shown to provide significant health benefits. The World Health Organization and the American Academy of Pediatrics promote human milk as the primary source of nutrition for newborns for at least 6 months. However the impact of human milk feeding for infants depends in part on the functional capacity of the motherís mammary gland. Both milk production capacity and expression of specific milk components that confer health benefits vary between women. This variation impacts the motherís ability to breastfeed according to recommendations and the value of her breastmilk to the recipient infant. A significant percentage of the cases of severe problems with lactation in women, could be due to failure of breast development and other patho-physiological mechanisms impairing breast maturation and milk secretion. In order to address this critical variability between women, it is necessary to understand the underlying mechanisms through which lactation is established and maintained or variation in mammary gland function arises.

The signaling pathways of development and differentiation induce epigenetic changes that contribute to the establishment of cellular expression profiles that are the basis of cell fate and lineage decisions. These epigenetic changes are manifested by DNA methylation, core histone tail modifications and changes to the chromatin conformation detectable by DNaseI hypersensitivity. Together this leads to changed access to DNA of factors important for signal transduction and gene transcription. The development of the mammary gland occurs primarily postnatally, and is tightly regulated by the hormones of puberty and pregnancy. These developmental processes include coordinate activation of specific expression patterns such as the milk protein genes during pregnancy. Windows in mammary gland development that have profound effects on tissue pathology and lactation capacity have been identified in animals model. For instance, pre-pubertal overfeeding can have lasting effects on lactation capacity. Placental insufficiency is in human the main cause of intrauterine growth restriction, which has been correlated to poor health outcome in later life. Animal models have shown that, besides effects on the unborn fetus, mammary gland function is affected. This in turn has effects on the neonateís health outcome. The extent to which variations in mammary development and lactation capacity are influenced by epigenetic regulation during development is unknown. Moreover, mechanisms of epigenetic control of gene expression in the mammary gland are not characterized.

We address basic mechanisms of epigenetic control of gene expression within the context of mammary biology. We use high-resolution, high-throughput methods to identify chromatin conformation and regulatory elements in mammary gland development and lactation by mapping epigenetic marks in vivo using DNA tiling microarrays (ChIp-chip, MeDIP, or DNase-chip). This will provide a basis for studies examining in detail the mechanisms by which chromatin remodeling contributes to breast development and lactation capacity. In addition, it enables studies aimed at integrating the hormonal signaling pathways and chromatin remodeling in normal mammary gland maturation, lactation, and disease. A more in-depth knowledge of the factors and pathways regulating mammary gland development and lactation will provide insight into how these processes can be manipulated to benefit mother and child.

Representative Publications

Montazer-Torbati, M.B., C. Hue-Beauvais, S. Droineau, M. Ballester, N. Coant, E. Aujean, M. Petitbarat, M. Rijnkels, and E. Devinoy, "Epigenetic modifications and chromatin loop organization explain the different expression profiles of the Tbrg4, WAP and Ramp3 genes". Exp Cell Res, (2008). 314(5): p. 975-87.

Ginger, M.R., A.N. Shore, A. Contreras, M. Rijnkels, J. Miller, M.F. Gonzalez-Rimbau, and J.M. Rosen, "A noncoding RNA is a potential marker of cell fate during mammary gland development". Proc Natl Acad Sci U S A, (2006). 103(15): p. 5781-6.

Kabotyanski, E.B., M. Huetter, W. Xian, M. Rijnkels, and J.M. Rosen, "Integration of prolactin and glucocorticoid signaling at the {beta}-casein promoter and enhancer by ordered recruitment of specific transcription factors and chromatin modifiers". Mol Endocrinol, (2006). 20(10): p. 2355-2368.

Hillier LW, ...Rijnkels M, et al. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature. 432(7018):695-716, 2004. Erratum in: Nature. 433(7027):777, 2005.

Rijnkels M, Elnitski L, Miller W, Rosen JM. Multispecies comparative analysis of a mammalian-specific genomic domain encoding secretory proteins. Genomics. 82(4):417-432, 2003.

Rijnkels, M, Elnitski, L., Miller, W. and Rosen J.M. (2003) Multi-species comparative analysis of a mammalian specific genomic domain encoding secreted proteins. Genomics, 82 , 417-432.

Rijnkels M (2002) Multi-species comparison of the casein gene loci and evolution of the casein gene family. J. Mammary Gland Biology and Neoplasia 7 (3): 327-345.

Rijnkels, M., Kooiman, P. M., Platenburg, G. J., van Dixhoorn, M., Nuijens, J. H., de Boer, H. A. andPieper, F. R. (1998). High level mammary gland specific expression of bovine alpha s1-casein in transgenic mice. Transgenic Res. 7 :5-14

Rijnkels, M. and Pieper, F. R. (1998). Casein gene-based mammary-gland specific transgene expression. In "Mammary gland transgenesis". Therapeutic protein production." (F. O. Castro and J. Janne, eds.), pp. 41-64, Springer-Verlag , Berlin .

Rijnkels, M., Wheeler, D., de Boer, H. A. and Pieper, F. R. (1997). Structure and expression of the mouse casein gene locus. Mamm. Genome 8 : 9-15. (BCM)

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