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Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells |
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| Authors: | Jiao Baowei Ma Hong Shokhirev Maxim N Drung Alexander Yang Qin Shin JongDae Lu Shaolei Byron Meg Kalantry Sundeep Mercurio Arthur M Lawrence Jeanne B Hoffmann Alexander Bach Ingolf |
| Institution: | 1 Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA 2 Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 3 Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA 4 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA 5 BioCircuits Institute, San Diego Center for Systems Biology of Cellular Stress Responses and Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA 6 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA |
| Abstract: | In female mouse embryos, somatic cells undergo a random form of X chromosome inactivation (XCI), whereas extraembryonic trophoblast cells in the placenta undergo imprinted XCI, silencing exclusively the paternal X chromosome. Initiation of imprinted XCI requires a functional maternal allele of the X-linked gene Rnf12, which encodes the ubiquitin ligase Rnf12/RLIM. We find that knockout (KO) of Rnf12 in female mammary glands inhibits alveolar differentiation and milk production upon pregnancy, with alveolar cells that lack RLIM undergoing apoptosis as they begin to differentiate. Genetic analyses demonstrate that these functions are mediated primarily by the paternal Rnf12 allele due to nonrandom maternal XCI in mammary epithelial cells. These results identify paternal Rnf12/RLIM as a critical survival factor for milk-producing alveolar cells and, together with population models, reveal implications of transgenerational epigenetic inheritance. |
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