RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes.

The onset of random X chromosome inactivation in mouse requires the switch from a symmetric to an asymmetric state, where the identities of the future inactive and active X chromosomes are assigned. This process is known as X chromosome choice. Here, we show that RIF1 and KAP1 are two fundamental factors for the definition of this transcriptional asymmetry. We found that at the onset of differentiation of mouse embryonic stem cells (mESCs), biallelic up-regulation of the long non-coding RNA Tsix weakens the symmetric association of RIF1 with the Xist promoter. The Xist allele maintaining the association with RIF1 goes on to up-regulate Xist RNA expression in a RIF1-dependent manner. Conversely, the promoter that loses RIF1 gains binding of KAP1, and KAP1 is required for the increase in Tsix levels preceding the choice. We propose that the mutual exclusion of Tsix and RIF1, and of RIF1 and KAP1, at the Xist promoters establish a self-sustaining loop that transforms an initially stochastic event into a stably inherited asymmetric X-chromosome state.

Emerging Roles of Repetitive and Repeat-Containing RNA in Nuclear and Chromatin Organization and Gene Expression.

Genomic repeats have been intensely studied as regulatory elements controlling gene transcription, splicing and genome architecture. Our understanding of the role of the repetitive RNA such as the RNA coming from genomic repeats, or repetitive sequences embedded in mRNA/lncRNAs, in nuclear and cellular functions is instead still limited. In this review we discuss evidence supporting the multifaceted roles of repetitive RNA and RNA binding proteins in nuclear organization, gene regulation, and in the formation of dynamic membrane-less aggregates. We hope that our review will further stimulate research in the consolidating field of repetitive RNA biology.

Protein tyrosine phosphatase 1b deficiency protects against hepatic fibrosis by modulating nadph oxidases.

Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B (PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B-/-) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B-/- mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment (Cd68, Adgre1 and Ccl2) compared to their wild-type (PTP1B+/+) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B-/- bone marrow (BM) into irradiated PTP1B+/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B-/- mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B-/- BM transplantation into PTP1B+/+ mice also led to a blockade of TGF-ß and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.