2019 Vol. 10, No. 6

Emerging studies support that RNA-binding proteins (RBPs) present a new scenario in human biology and pathogenesis. However, RBPs are still a Cinderella of cardiovascular diseases. In this issue, Liu et al. find that targeted deletion of RNA binding protein Rbm24 in postnatal heart leads to dilated cardiomyopathy (DCM). Global analysis reveals knockout of Rbm24 results in mis-regulation of alternative splicing networks, including a subset of genes encoding heart sarcomeric proteins, such as Titin, the major disease gene of DCM and heart failure. This report may represent a novel pathway to cardiomyopathy and deserve more attention in further genetic screenings in human patients (see also the "COMMENTARY" by Gaertner et al., this issue).
In memory of Prof. C. C. Li
Zhi Xia, Juan Tian, Xiaoling Wang, Huanming Yang
2019, 10(6): 389-392. doi: 10.1007/s13238-018-0583-y
Screening for mutations in human cardiomyopathy-is RBM24 a new but rare disease gene?
Anna Gaertner, Andreas Brodehl, Hendrik Milting
2019, 10(6): 393-394. doi: 10.1007/s13238-018-0590-z
Research articles
Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch
Daisuke Aki, Qian Li, Hui Li, Yun-Cai Liu, Jee Ho Lee
2019, 10(6): 395-404. doi: 10.1007/s13238-018-0586-8
Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.
RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy
Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu
2019, 10(6): 405-416. doi: 10.1007/s13238-018-0578-8
RNA splicing contributes to a broad spectrum of posttranscriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.
Chemical screen identifies a geroprotective role of quercetin in premature aging
Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu
2019, 10(6): 417-435. doi: 10.1007/s13238-018-0567-y
Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1-and Pgc-1α-mediated regulation of Glut2
Xinhui Wang, Hong Gao, Wenhui Wu, Enjun Xie, Yingying Yu, Xuyan He, Jin Li, Wanru Zheng, Xudong Wang, Xizhi Cao, Zhuoxian Meng, Ligong Chen, Junxia Min, Fudi Wang
2019, 10(6): 436-449. doi: 10.1007/s13238-018-0580-1
Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
In vivo tunable CRISPR mediates efficient somatic mutagenesis to generate tumor models
Xiaomeng An, Linlin Li, Sen Wu
2019, 10(6): 450-454. doi: 10.1007/s13238-018-0579-7
The effect of clinical-grade retinal pigment epithelium derived from human embryonic stem cells using different transplantation strategies
Lei Wang, Wei Wu, Qi Gu, Zengping Liu, Qiyou Li, Zhongwen Li, Jinhui Fang, Wenjing Liu, Jun Wu, Ying Zhang, Liu Wang, Haiwei Xu, Wei Li, Baoyang Hu, Qi Zhou, Zhengqin Yin, Jie Hao
2019, 10(6): 455-460. doi: 10.1007/s13238-018-0606-8
In vitro transcribed sgRNA causes cell death by inducing interferon release
Wei Mu, Na Tang, Chen Cheng, Wen Sun, Xiaofei Wei, Haoyi Wang
2019, 10(6): 461-465. doi: 10.1007/s13238-018-0605-9