derangement of a factor upstream of rarα triggers the repression of a pleiotropic epigenetic network错乱的因子上游rarα触发多向性的表观遗传网络的镇压.pdfVIP

Derangement of a Factor Upstream of RARa Triggers the Repression of a Pleiotropic Epigenetic Network . . . Francesca Corlazzoli , Stefano Rossetti , Gaia Bistulfi , Mingqiang Ren, Nicoletta Sacchi* Cancer Genetics Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America Abstract Background: Chromatin adapts and responds to extrinsic and intrinsic cues. We hypothesize that inheritable aberrant chromatin states in cancer and aging are caused by genetic/environmental factors. In previous studies we demonstrated that either genetic mutations, or loss, of retinoic acid receptor alpha (RARa), can impair the integration of the retinoic acid (RA) signal at the chromatin of RA-responsive genes downstream of RARa, and can lead to aberrant repressive chromatin states marked by epigenetic modifications. In this study we tested whether the mere interference with the availability of RA signal at RARa, in cells with an otherwise functional RARa, can also induce epigenetic repression at RA-responsive genes downstream of RARa. Methodology/Principal Findings: To hamper the availability of RA at RARa in untransformed human mammary epithelial cells, we targeted the cellular RA-binding protein 2 (CRABP2), which transports RA from the cytoplasm onto the nuclear RARs. Stable ectopic expression of a CRABP2 mutant unable to enter the nucleus, as well as stable knock down of endogenous CRABP2, led to the coordinated transcriptional repression of a few RA-responsive genes downstream of RARa. The chromatin at these genes acquired an exacerbated repressed state, or state ‘‘of no return’’. This aberrant state is unresponsive to RA, and therefore differs from the physiologically repressed, yet ‘‘poised’’ state, which is resp