Submitted to: Experimental Cell Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/6/2008
Publication Date: 1/12/2008
Citation: Montazer-Torbati, M.B., Hue-Beauvais, C., Droineau, S., Ballester, M., Coant, N., Aujean, E., Petitbarat, M., Rijnkels, M., Devinoy, E. 2008. Epigenetic modifications and chromatin loop organization explain the different expression profiles of the Tbrg4, WAP and Ramp3 genes. Experimental Cell Research. 314:975-987. Interpretive Summary: Whey Acidic Protein (WAP) is present in milk of a number of mammals. The gene encoding for WAP is only expressed in the mammary gland during lactation regulated by the hormones that control lactation. In the genome the WAP gene is located between 2 genes that are expressed in all tissues. We show that the way the DNA containing the WAP genes is packaged in the nucleus of the cell may play a role in ensuring that this gene is only expressed in the mammary gland during lactation and the neighboring genes in all tissues.
Technical Abstract: Whey Acidic Protein (WAP) gene expression is specific to the mammary gland and regulated by lactogenic hormones to peak during lactation. It differs markedly from the more constitutive expression of the two flanking genes, Ramp3 and Tbrg4. Our results show that the tight regulation of WAP gene expression parallels variations in the chromatin structure and DNA methylation profile throughout the Ramp3–WAP–Tbrg4 locus. Three Matrix Attachment Regions (MAR) have been predicted in this locus. Two of them are located between regions exhibiting open and closed chromatin structures in the liver. The third, located around the transcription start site of the Tbrg4 gene, interacts with topoisomerase II in HC11 mouse mammary cells, and in these cells anchors the chromatin loop to the nuclear matrix. Furthermore, if lactogenic hormones are present in these cells, the chromatin loop surrounding the WAPgene is more tightly attached to the nuclear structure, as observed after a high salt treatment of the nuclei and the formation of nuclear halos. Taken together, our results point to a combination of several epigenetic events that may explain the differential expression pattern of the WAP locus in relation to tissue and developmental stages.