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The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Introduction: The functional roles and mechanism of the XIST in osteoarthritis and the chondrogenic differentiation of BMSCs were clarified. Methods: The expression levels of XIST, TAF15, FUT1 and YY1 were detected through quantitative RT-PCR. The protein expression of Sox9, ACAN, COL2A1 and FUT1 were detected by western blot and immunohistochemistry. The damage of cartilage tissue was detected by HE staining, and Safranin O-fast green. Alcian-Blue and Alizarin red S staining were performed to evaluate BMSCs chondrogenic differentiation. The relationship between XIST and TAF15, XIST and TAF15 were analyzed by RNA immunoprecipitation assay. Luciferase reporter assays and chromatin immunoprecipitation were performed to detect the interaction relationship between XIST and YY1. In addition, osteoarthritis mice were built to assess the function of XIST in vivo. Results: The levels of XIST, TAF15 and FUT1 were upregulated in cartilage tissues from osteoarthritis patient. The level of XIST was decreased in BMSCs during chondrogenic differentiation. XIST overexpression inhibited the chondrogenic differentiation of BMSCs. Moreover, silencing of FUT1 reversed the effects of XIST overexpression on BMSCs chondrogenic differentiation. Mechanistically, in BMSCs, YY1 induced the expression of XIST in BMSCs, and XIST regulated FUT1 mRNA stability through targeting TAF15. Furthermore, silencing of XIST alleviated the symptoms of cartilage injury in OA mice. Conclusion: Taken together, these results suggested that YY1 induced XIST was closely related to the chondrogenic differentiation of BMSCs and the progression of osteoarthritis by TAF15/FUT1 axis, and may be a new OA therapeutic target.

Lung cancer is a major cause of cancer-associated deaths worldwide, and lung adenocarcinoma (LUAD) is the most common lung cancer subtype. Micro RNAs (miRNAs) regulate the pattern of gene expression in multiple cancer types and have been explored as potential drug development targets. To develop an oncomiR-based panel, we identified miRNA candidates that show differential expression patterns and are relevant to the worse 5-year overall survival outcomes in LUAD patient samples. We further evaluated various combinations of miRNA candidates for association with 5-year overall survival and identified a four-miRNA panel: miR-9-5p, miR-1246, miR-31-3p, and miR-3136-5p. The combination of these four miRNAs outperformed any single miRNA for predicting 5-year overall survival (hazard ratio [HR]: 3.47, log-rank p-value = 0.000271). Experiments were performed on lung cancer cell lines and animal models to validate the effects of these miRNAs. The results showed that singly transfected antagomiRs largely inhibited cell growth, migration, and invasion, and the combination of all four antagomiRs considerably reduced cell numbers, which is twice as effective as any single miRNA-targeted transfected. The in vivo studies revealed that antagomiR-mediated knockdown of all four miRNAs significantly reduced tumor growth and metastatic ability of lung cancer cells compared to the negative control group. The success of these in vivo and in vitro experiments suggested that these four identified oncomiRs may have therapeutic potential.

BackgroundChronic calcium channel blockers (CCBs) are indicated in children with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population.MethodsPatients aged 3 months to 18 years who were diagnosed with IPAH/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed.ResultsThirty-two eligible children were enrolled in the study, with a median age of 9 (6–11) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8–16.8) mg/kg/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5–28.5) mg/kg/day vs. 12.7 (6.6–14.4) mg/kg/day, P < 0.05. Patients were followed up for a median period of 6.2 (2.6–10.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported.ConclusionDiltiazem was used in a very high dose for eligible children with IPAH/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.