Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genet. 2012;8(7):e1002840. doi: 10.1371/journal.pgen.1002840. Epub 2012 Jul 26.
Pregnancy-induced noncoding RNA (PINC) and retinoblastoma-associated protein 46 (RbAp46) are upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that remain in the regressed lobules following involution. The cells that survive involution are thought to function as alveolar progenitor cells that rapidly differentiate into milk-producing cells in subsequent pregnancies, but it is unknown whether PINC and RbAp46 are involved in maintaining this progenitor population. Here, we show that, in the post-pubertal mouse mammary gland, mPINC is enriched in luminal and alveolar progenitors. mPINC levels increase throughout pregnancy and then decline in early lactation, when alveolar cells undergo terminal differentiation. Accordingly, mPINC expression is significantly decreased when HC11 mammary epithelial cells are induced to differentiate and produce milk proteins. This reduction in mPINC levels may be necessary for lactation, as overexpression of mPINC in HC11 cells blocks lactogenic differentiation, while knockdown of mPINC enhances differentiation. Finally, we demonstrate that mPINC interacts with RbAp46, as well as other members of the polycomb repressive complex 2 (PRC2), and identify potential targets of mPINC that are differentially expressed following modulation of mPINC expression levels. Taken together, our data suggest that mPINC inhibits terminal differentiation of alveolar cells during pregnancy to prevent abundant milk production and secretion until parturition. Additionally, a PRC2 complex that includes mPINC and RbAp46 may confer epigenetic modifications that maintain a population of mammary epithelial cells committed to the alveolar fate in the involuted gland.
妊娠诱导的非编码 RNA（PINC）和视网膜母细胞瘤相关蛋白 46（RbAp46）在妊娠期间乳腺的肺泡细胞中上调，并在退化小叶中仍存在的肺泡细胞中持续存在。据认为，存活下来的细胞是作为肺泡祖细胞，在随后的妊娠中迅速分化为产奶细胞，但尚不清楚 PINC 和 RbAp46 是否参与维持这种祖细胞群体。在这里，我们表明，在青春期后的小鼠乳腺中，mPINC 富集在腔和肺泡祖细胞中。mPINC 水平在整个怀孕期间增加，然后在早期哺乳期下降，此时肺泡细胞经历终末分化。因此，当 HC11 乳腺上皮细胞被诱导分化并产生乳蛋白时，mPINC 的表达显著降低。这种 mPINC 水平的降低可能对泌乳是必要的，因为 HC11 细胞中 mPINC 的过表达会阻断泌乳分化，而 mPINC 的敲低会增强分化。最后，我们证明 mPINC 与 RbAp46 以及多梳抑制复合物 2（PRC2）的其他成员相互作用，并鉴定了 mPINC 表达水平调节后差异表达的潜在靶标。总之，我们的数据表明，mPINC 在妊娠期间抑制肺泡细胞的终末分化，以防止大量乳汁产生和分泌，直到分娩。此外，包含 mPINC 和 RbAp46 的 PRC2 复合物可能赋予维持参与退化腺中肺泡命运的乳腺上皮细胞群体的表观遗传修饰。
