TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk.

TDP-43 is an RNA/DNA-binding protein that forms aggregates in various brain disorders. TDP-43 engages in many aspects of RNA metabolism, but its molecular roles in regulating genes and transposable elements (TEs) have not been extensively explored. Chronic TDP-43 knockdown impairs cell proliferation and cellular responses to DNA damage. At the molecular level, TDP-43 chronic deficiency affects gene expression either locally or distally by concomitantly altering the crosstalk between R-loops and 5-hydroxymethylcytosine (5hmC) in gene bodies and long-range enhancer/promoter interactions. Furthermore, TDP-43 knockdown induces substantial disease-relevant TE activation by influencing their R-loop and 5hmC homeostasis in a locus-specific manner. Together, our findings highlight the genomic roles of TDP-43 in modulating R-loop-5hmC coordination in coding genes, distal regulatory elements, and TEs, presenting a general and broad molecular mechanism underlying the contributions of proteinopathies to the etiology of neurodegenerative disorders.

Deciphering the implications of mitophagy-related signatures in clinical outcomes and microenvironment heterogeneity of clear cell renal cell carcinoma.

BACKGROUND: The role of mitophagy in various cancer-associated biological processes is well recognized. Nonetheless, the comprehensive implications of mitophagy in clear cell renal cell carcinoma (ccRCC) necessitate further exploration. METHODS: Based on the transcriptomic data encompassing 25 mitophagy-related genes (MRGs), we identified the distinct mitophage patterns in 763 ccRCC samples. Subsequently, a mitophage-related predictive signature with machine learning algorithms was constructed, designated as RiskScore, to quantify the individual mitophagy status in ccRCC patients. Employing multispectral immunofluorescence (mIF) and immunohistochemistry (IHC) staining, we detected the effect of PTEN-induced putative kinase 1 (PINK1) in the prognosis and immune microenvironment of ccRCC. RESULTS: Our analysis initially encompassed a comprehensive assessment of the expression profiling, genomic variations, and interactions among the 25 MRGs in ccRCC. Subsequently, the consensus clustering algorithm was applied to stratify ccRCC patients into three clusters with distinct prognostic outcomes, tumor microenvironment (TME) characteristics, and underlying biological pathways. We screened eight pivotal genes (CLIC4, PTPRB, SLC16A12, ENPP5, FLRT3, HRH2, PDK4, and SCD5) to construct a mitophagy-related predictive signature, which showed excellent prognostic value for ccRCC patients. Moreover, patient subgroups divided by the RiskScore showed contrasting expression levels of immune checkpoints (ICPs), abundance of immune cells, and immunotherapy response. Additionally, a nomogram was established with robust predictive power integrating the RiskScore and clinical features. Notably, we observed that PINK1 expression markedly correlated with favorable treatment response and advanced maturation stages of tertiary lymphoid structures, which potentially shed light on enhancing anti-tumor immunity of ccRCC. CONCLUSION: Collectively, this study initially developed a signature associated with mitophagy, which demonstrated an excellent ability to predict the clinical prognosis, TME characterization, and responsiveness to targeted therapy and immunotherapy for ccRCC patients. Of particular note is the pivotal role of PINK1 in mediating the treatment response and immune microenvironment for ccRCC patients.

Bioinformatic analyzes and validation of cystathionine gamma-lyase as a prognostic biomarker and related to immune infiltrates in hepatocellular carcinoma.

Background: The role of cystathionine γ-lyase (CTH) in the prognosis and immune invasion of hepatocellular carcinoma (HCC) remains poorly understood. Methods: In this study, the clinical data of patients with HCC were analyzed, and the expression level of CTH was compared between HCC and normal tissues using the R package and various databases. Results: We found that CTH expression was significantly decreased in HCC compared with normal tissues, and its expression was associated with various clinicopathological factors, including tumor stage, gender, tumor status, residual tumor, histologic stage, race, alpha-fetoprotein (AFP), albumin, drinking, and smoking. Our results suggest that CTH might be a protective factor for the survival of patients with HCC. Further functional analysis revealed that high CTH expression was enriched in the Reactome signaling by interleukins and the Reactome neutrophil degranulation. Moreover, CTH expression was closely correlated with a variety of immune cells, including a negative correlation with the CD56 (bright) NK cells and follicular helper T cell (TFH), while a positive correlation with Th17 cells and central memory T cell (Tcm). High expression of CTH in immune cells predicted a better prognosis of HCC. Our findings further indicated Pyridoxal phosphate, l-cysteine, Carboxymethylthio-3-(3-chlorophenyl)-1,2,4-oxadiazol, 2-[(3-Hydroxy-2-Methyl-5-Phosphonooxymethyl-Pyridin-4-Ylmethyl)-Imino]-5-phosphono-pent-3-enoic acid and L-2-amino-3-butynoic acid as potential target candidate medications for HCC treatment based on CTH. Conclusion: Our study suggests that CTH can serve as a biomarker to predict the prognosis and immune infiltration of HCC.

The effectiveness of motherwort injection in preventing postabortion hemorrhage after induced abortion: A protocol for systematic review and meta-analysis.

BACKGROUND: Unintended pregnancy is a problem that women encounter throughout their reproductive age. Excessive and prolonged uterine bleeding is one of the most common and critical adverse reactions of induced abortion, for it increases the risk of anemia and intrauterine infection. To provide reliable clinical evidence, we performed a protocol for systematic review and meta-analysis to evaluate the hemostatic effect of motherwort in postabortion. METHODS: This review protocol has been registered in the international prospective register of systematic reviews. The statement of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols will be used as guidelines for reporting present review protocol. Original clinical randomized controlled trials assessing the beneficial effects and safety of motherwort on induced abortion will be included. Databases searched include China National Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang Database, China Biological Medicine Database, PubMed, and EMBASE Database and Cochrane Central Register of Controlled Trials. Cochrane collaboration tool is used to assess the risk of bias of included randomized controlled trials. All calculations are carried out with Stata 11.0 (The Cochrane Collaboration, Oxford, United Kingdom). RESULTS: This systematic review and meta-analysis will provide a detailed summary of the current evidence related to the efficacy of motherwort injection preventing postabortion hemorrhage after induced abortion. CONCLUSION: This evidence will be useful to practitioners, patients, and health policy-makers regarding the use of motherwort injection in induced abortion.

Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.

The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1-F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the Fto gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in Fto results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of Fto can lead to the same phenotypes as genetic variants.

Integrating machine learning to construct aberrant alternative splicing event related classifiers to predict prognosis and immunotherapy response in patients with hepatocellular carcinoma.

Introduction: In hepatocellular carcinoma (HCC), alternative splicing (AS) is related to tumor invasion and progression. Methods: We used HCC data from a public database to identify AS subtypes by unsupervised clustering. Through feature analysis of different splicing subtypes and acquisition of the differential alternative splicing events (DASEs) combined with enrichment analysis, the differences in several subtypes were explored, cell function studies have also demonstrated that it plays an important role in HCC. Results: Finally, in keeping with the differences between these subtypes, DASEs identified survival-related AS times, and were used to construct risk proportional regression models. AS was found to be useful for the classification of HCC subtypes, which changed the activity of tumor-related pathways through differential splicing effects, affected the tumor microenvironment, and participated in immune reprogramming. Conclusion: In this study, we described the clinical and molecular characteristics providing a new approach for the personalized treatment of HCC patients.

Transcriptome Profiles Reveal a 12-Signature Metabolic Prediction Model and a Novel Role of Myo-Inositol Oxygenase in the Progression of Prostate Cancer.

Prostate adenocarcinoma (PRAD) is an extremely common type of cancer in the urinary system. Here, we aimed to establish a metabolic signature to identify novel targets in a predictive model of PRAD patients. A total of 133 metabolic differentially expressed genes (MDEGs) were identified with significant prognostic value. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a 12-mRNA signature model, a metabolic prediction model (MPM), in 491 PRAD patients. The risk score of the MPM significantly predicted the progression of PRAD patients (p < 0.001, area under the curve (AUC) = 0.745). Furthermore, myo-inositol oxygenase (MIOX), the most prominently upregulated metabolic enzyme and hub gene in the protein-protein interaction network of the MPM, showed significant prognostic implications. Next, MIOX expression in normal prostate tissues was lower than in PRAD tissues, and high MIOX expression was significantly associated with disease progression (p = 0.005, HR = 2.274) in 81 PRAD patients undergoing first-line androgen receptor signaling inhibitor treatment from the Renji cohort. Additionally, MIOX was significantly involved in the abnormal immune infiltration of the tumor microenvironment and associated with the DNA damage repair process of PRAD. In conclusion, this study provides the first opportunity to comprehensively elucidate the landscape of prognostic MDEGs, establish novel prognostic modeling of MPM using large-scale PRAD transcriptomic data, and identify MIOX as a potential prognostic target in PRAD patients from multiple cohorts. These findings help manage risk assessment and provide valuable insights into treatment strategies for PRAD.

A new method of monitoring catheter-directed thrombolysis for deep venous thrombosis-application of D-dimer and fibrinogen testing.

BACKGROUND: Catheter-directed thrombolysis (CDT) is one of the main treatment methods for acute deep venous thrombosis (DVT), which has the characteristics of long treatment time and large dosage of thrombolytic drugs. In the absence of good monitoring methods, problems such as low thrombolytic efficiency and high risk of bleeding are easy to occur. OBJECTIVE: To evaluate the value of D-dimer (D-D) and fibrinogen (FIB) testing as a thrombolysis-monitoring method during CDT for acute DVT. METHODS: Twenty patients with acute DVT were divided into group A and group B. During CDT, the D-D and FIB testing every 8 h were used in group A, and the venography and FIB testing every 24 h in group B. The thrombolysis rate, thrombolysis time, urokinase dosage, and X-ray radiation dose were compared. RESULTS: The thrombolysis rate in group A was significantly higher than that in group B (p < 0.05), but the number of venography and radiation dose were significantly lower than those in group B (p < 0.05). CONCLUSION: D-D and FIB testing can improve the thrombolysis rate, reduce the risk of bleeding, and decrease the number of angiograms and X-ray radiation dose during CDT.

Association of screen time-based sedentary behavior and the risk of depression in children and adolescents: Dose-response meta-analysis

ABSTRACT Purpose: We aimed to find the association between screen time (ST)-based sedentary behavior and depression in children and adolescents. Methods: PubMed, Embase, and Web of science database were searched to find eligible studies until April 25, 2021. Data extraction was conducted by two investigators independently, followed by quality assessment for included studies. Odd ration (OR) and 95% confidence intervals (CI) were regarded as effect size index. Heterogeneity test was conducted using Cochran' s Q test and I2 test. Least squares trend estimation method was used for dose-response meta-analysis. All statistical analyses were conducted using Stata12.0 software. Results: Totally 22 articles containing 197,673 cases were included. The pooled results displayed that there was a significant positive correlation between ST and depression [OR (95%CI) = 1.24 (1.11, 1.38), P < 0.001]. Similar results were observed for watching television (TV), computer use (CU), computer game (CG)/video game (VG) and internet use (IU)/mobile phone (MP) time. Dose-response meta-analysis showed that take 1 hour/day as control, the risk of depression went down and then went up as sedentary time increased for ST (P > 0.05). The risk of depression was significantly increased when TV time beyond 4.5 hours/day (P < 0.05), or CU time beyond 0.5 hours/day (P < 0.05), or CG/VG time beyond 2 hours/day (P < 0.05), or IU/MP time beyond 0.5 hours/day (P < 0.05). Conclusion: ST-based sedentary behavior was associated with the risk of depression in a non-linear dose-response manner for children and adolescents.

Correlation of serum uric acid, cystatin C and high-sensitivity C-reactive protein with cognitive impairment in lacunar cerebral infarction.

OBJECTIVE: To study the correlation of serum uric acid (UA), cystatin C (Cys-C) and high-sensitivity C-reactive protein (hs-CRP) with cognitive impairment in lacunar cerebral infarction. METHODS: Total 198 patients with lacunar cerebral infarction were selected and divided into 4 groups according to their cognitive function, with 65 cases in the normal group, 72 cases in the mild cognitive impairment group, 38 cases in the moderate cognitive impairment group and 23 cases in the severe cognitive impairment group. The hs-CRP, serum UA, Cys-C and Montreal Cognitive Assessment (MoCA) were measured upon admission. RESULTS: There were statistical differences in hs-CRP, UA and Cys-C among the four groups (all P<0.001). MoCA was negatively correlated with hs-CRP, UA and Cys-C (all P<0.001). Multivariate logistic regression analysis showed that elevated levels of hs-CRP, UA and Cys-C were the influencing factors of cognitive impairment in patients with lacunar cerebral infarction (all P<0.05). CONCLUSION: The levels of hs-CRP, UA and Cys-C in patients with lacunar cerebral infarction increase with the aggravation of cognitive impairment, and high hs-CRP, UA and Cys-C are independent risk factors of cognitive impairment in patients with lacunar cerebral infarction.

Regulation of 3D chromatin organization by CTCF.

Studies of nuclear architecture using chromosome conformation capture methods have provided a detailed view of how chromatin folds in the 3D nuclear space. New variants of this technology now afford unprecedented resolution and allow the identification of ever smaller folding domains that offer new insights into the mechanisms by which this organization is established and maintained. Here we review recent results in this rapidly evolving field with an emphasis on CTCF function, with the goal of gaining a mechanistic understanding of the principles by which chromatin is folded in the eukaryotic nucleus.

Tenacissoside H promotes neurological recovery of cerebral ischaemia/reperfusion injury in mice by modulating inflammation and oxidative stress via TrkB pathway.

Cerebral ischaemia/reperfusion (I/R)-induced acute brain injury remains a troublesome condition in clinical practice. The present study aimed to investigate the protective effect of tenacissoside H (TH) on I/R-induced cerebral injury in mice. Here, a mouse model of middle cerebral artery occlusion (MCAO) was established by an improved Longa-Zea method. TH was given by intraperitoneal injection once a day within 1 week before establishing the mouse MCAO model. The neurological functions of mice were evaluated and the apoptosis of neurons was also detected by the TUNEL method and Nissl's staining. ELISA and western blot were used to detect the expression of inflammatory factors, oxidation factors and proteins in the cerebral ischaemic cortex. The results revealed that TH dose-dependently reduced neurological impairment, neuron apoptosis and brain oedema induced by MCAO. Furthermore, TH attenuated the expression of pro-inflammatory cytokines (including interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α), iNOS and nuclear factor (NF)-κB while increased production of anti-inflammatory cytokines (IL-4, IL-10 and BDNF) and proteins of tropomyosin-related kinase receptor B (TrkB) and PPARγ. Nevertheless, after the addition of TrkB inhibitor, the effects of TH above were mostly restrained. In conclusion, TH can protect mice against I/R-induced neurological impairments via modulating inflammation and oxidative stress through TrkB signalling.

Magnetic resonance-guided ablation of liver tumors: A systematic review and pooled analysis.

PURPOSE: The purpose of this study is to study the clinical outcomes of different types of magnetic resonance (MR)-guided ablation for the treatment of liver tumors by performing a systematic review and pooled analysis. MATERIALS AND METHODS: A comprehensive literature search was performed for clinical trials published from January 1997 to October 2019 in PubMed, the Web of Science, Embase, and the Cochrane Library. Pooled analyses were performed to obtain the complete ablation (CA), complication, progression-free survival (PFS), and overall survival (OS) rates. RESULTS: Thirty studies were eligible, including four studies on MR-guided microwave ablation (MWA); 14 studies on MR-guided radiofrequency ablation (RFA); one study on both MR-guided MWA and RFA; eight studies on MR-guided, laser-induced thermotherapy (LITT); two studies on MR-guided percutaneous cryoablation (PC); and one study on MR-guided percutaneous ethanol injection (PEI). The CA rates in patients who underwent RFA, MWA, LITT, PC, and PEI were 95.60%, 98.86%, 77.78%, 47.92%, and 85.71%, respectively. The most frequent complications were pain (27.66%, 13/47) and postablation syndrome (27.66%, 13/47) in the PC group; pleural effusion (8.11%, 119/1,468) and subcapsular hematoma (2.25%, 33/1,468) in the LITT group; pleural effusion (2.67%, 2/75) in the MWA group; and subcapsular hematoma (4.18%, 20/478) and post-ablation syndrome (2.93%, 14/478) in the RFA group. There were few studies reporting PFS and OS. CONCLUSIONS: MR-guided ablation is a practicable alternative treatment for liver tumors, especially MR-guided RFA and MWA, which have high rates of CA and low occurrences of complications.

Mesenchymal stem cells-derived exosomes improve pregnancy outcome through inducing maternal tolerance to the allogeneic fetus in abortion-prone mating mouse.

Recurrent pregnancy loss (RPL) is three or more times of consecutive spontaneous loss of pregnancy. The underlying cause is complicated and the etiology of over 50% of RPL patients is unclear. In the present study, bone marrow mesenchymal stem cells were isolated from CBA/J female mice and exosomes were isolated from cell culture medium by ultracentrifugation. CBA/J female mice were paired with male DBA/2 to generate abortion prone mouse model, and CBA/J females paired with male BALB/c mice were used as control. Exosomes were injected through uterine horns into pregnant CBA/J mice on day 4.5 of gestation in abortion-prone matting. On day 13.5 of pregnancy, abortion rates were calculated and the level of transforming growth factor-ß (TGF-ß), interleukin 10 (IL-10), interferon g (IFN-γ), and tumor necrosis factor a (TNF-α) in CD4+ T cells and macrophages in deciduas were evaluated by flow cytometry. Exosomes injection improved the pregnancy outcomes in abortion prone mice. The IL-4 and IL-10 levels on CD4+ T cells were upregulated in the maternal-fetal interface; meanwhile, the TNF-α and IFN-γ levels on CD4+ T cells were reduced. The IL-10 level was increased and IL-12 was reduced on the monocytes that separated from deciduas. miR-101 level was increased in the CD4+ T cells in the deciduas. In conclusion, the treatment of ESCs-derived exosomes modulates T cells' function and macrophages activities in the maternal-fetal interface that resulted in a decreased embryo resorption rate, and provides a therapeutic potential to treat RPL.

MRI-Guided Cryoablation of Hepatic Dome Hepatocellular Carcinomas Using 1-T Open High-Field-Strength Scanner.

OBJECTIVE. The objective of our study was to prospectively evaluate the feasibility, safety, and effectiveness of 1-T open MRI-guided percutaneous cryoablation of hepatic dome hepatocellular carcinomas (HCCs). SUBJECTS AND METHODS. Thirty-seven patients with 37 hepatic dome HCCs underwent MRI-guided percutaneous cryoablations. MR fluoroscopy with a freehand technique was applied in the procedure. All lesions ranged in size from 8 to 38 mm. Patients were followed for at least 12 months after cryoablation or until death. Survival period, local tumor control, and complications were recorded. RESULTS. MRI-guided percutaneous cryoablation procedures were successfully performed on all 37 lesions. The technical success rate was 100%. The median follow-up time was 21.0 months (range, 10-26 months). Two patients with local tumor progression at the 4th and 11th month after the procedure were treated with a supplementary cryoablation. One patient died of upper gastrointestinal hemorrhage at the 10th month after cryoablation. Local tumor progression and overall survival rates were 2.7% (1/37) and 100% (37/37) at 6 months and 5.4% (2/37) and 97.3% (36/37) at 1 year, respectively. Postoperative hydrothorax that required chest tube drainage occurred in two patients; no other severe complications occurred. CONCLUSION. Cryoablation of hepatic dome HCCs with 1-T open MRI guidance is a feasible, safe, and effective therapy method.

Real-time MR-guided brain biopsy using 1.0-T open MRI scanner.

OBJECTIVES: To evaluate the safety, feasibility and diagnostic performance of real-time MR-guided brain biopsy using a 1.0-T open MRI scanner. METHODS: Medical records of 86 consecutive participants who underwent brain biopsy under the guidance of a 1.0-T open MRI scanner with real-time and MR fluoroscopy techniques were evaluated retrospectively. All procedures were performed under local anaesthesia and intravenous conscious sedation. Diagnostic yield, diagnostic accuracy, complication rate and procedure duration were assessed. The lesions were divided into two groups according to maximum diameters: ≤ 1.5 cm (n = 16) and > 1.5 cm (n = 70). The two groups were compared using Fisher's exact test. RESULTS: Diagnostic yield and diagnostic accuracy were 95.3% and 94.2%, respectively. The diagnostic yield of lesions ≤ 1.5 cm and > 1.5 cm were 93.8% and 95.7%, respectively. There was no significant difference in diagnostic yield between the two groups (p > 0.05). Mean procedure duration was 41 ± 5 min (range 33-49 min). All biopsy needles were placed with one pass. Complication rate was 3.5% (3/86). Minor complications included three cases of a small amount of haemorrhage. No serious complications were observed. CONCLUSIONS: Real-time MR-guided brain biopsy using a 1.0-T open MRI scanner is a safe, feasible and accurate diagnostic technique for pathological diagnosis of brain lesions. The procedure duration is shortened and biopsy work flow is simplified. It could be considered as an alternative for brain biopsy. KEY POINTS: • Real-time MRI-guided brain biopsy using a 1.0-T open MRI scanner is safe, feasible and accurate. • No serious complications occurred in real-time MRI-guided brain biopsy. • Procedure duration is shortened and biopsy work flow is simplified.

N6-Methyladenosines Modulate A-to-I RNA Editing.

N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two types of adenosine modifications is largely unknown. Here we show a global A-to-I difference between m6A-positive and m6A-negative RNA populations. Both the presence and extent of A-to-I sites in m6A-negative RNA transcripts suggest a negative correlation between m6A and A-to-I. Suppression of m6A-catalyzing enzymes results in global A-to-I RNA editing changes. Further depletion of m6A modification increases the association of m6A-depleted transcripts with adenosine deaminase acting on RNA (ADAR) enzymes, resulting in upregulated A-to-I editing on the same m6A-depleted transcripts. Collectively, the effect of m6A on A-to-I suggests a previously underappreciated interplay between two distinct and abundant RNA modifications, highlighting a complex epitranscriptomic landscape.

Targeting of growth factors in the treatment of hepatocellular carcinoma: The potentials of polysaccharides.

Hepatocellular carcinoma (HCC) has become a leading cause of cancer-associated mortality worldwide and is thus of great concern. Although various chemotherapeutic drugs are currently used for the treatment of HCC, severe side effects associated with these treatments have prompted interest in novel therapies, including the use of certain biological macromolecules such as polysaccharides. Several studies have shown that polysaccharides have anticancer and antiproliferative effects on HCC. Vascular endothelial growth factor, transforming growth factor ß, epidermal growth factor and fibroblast growth factor may be effective targets for polysaccharides and may modulate tumor growth and immunity through increasing the expression levels of cytokines. The present review focuses on the ways in which growth factors contribute to the development of HCC, and on the anti-growth factor activities of natural and synthetic polysaccharides, as well as their effect on proinflammatory cytokines.

RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression.

Protein translation regulation has essential roles in inflammatory responses, cancer initiation and the pathogenesis of several neurodegenerative disorders. However, the role of the regulation of protein translation in mammalian skeleton development has been rarely elaborated. Here we report that the lack of the RNA-binding protein sterile alpha motif domain containing protein 4 (SAMD4) resulted in multiple developmental defects in mice, including delayed bone development and decreased osteogenesis. Samd4-deficient mesenchymal progenitors exhibit impaired osteoblast differentiation and function. Mechanism study demonstrates that SAMD4 binds the Mig6 mRNA and inhibits MIG6 protein synthesis. Consistent with this, Samd4-deficient cells have increased MIG6 protein level and knockdown of Mig6 rescues the impaired osteogenesis in Samd4-deficient cells. Furthermore, Samd4-deficient mice also display chondrocyte defects, which is consistent with the regulation of MIG6 protein level by SAMD4. These findings define SAMD4 as a previously unreported key regulator of osteoblastogenesis and bone development, implying that regulation of protein translation is an important mechanism governing skeletogenesis and that control of protein translation could have therapeutic potential in metabolic bone diseases, such as osteoporosis.

Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins.

We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5' small nucleolar RNA (snoRNA) capped and 3' polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3' processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5' end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis.