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Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation of adult cardiomyocytes is crucially useful for cardiac repair after MI. Here, we found that miR-130b-5p was highly expressed in mouse embryonic and neonatal hearts and able to promote cardiomyocyte proliferation both in vitro and in vivo. Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, we found that overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after MI. These studies thus revealed the critical role of miR-130b-5p and its targeted MAPK-ERK signaling in the cardiomyocyte proliferation of adult hearts and proved that miR-130b-5p could be a potential target for cardiac repair after MI. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in‐depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single‐cell RNA and TCR sequencing of six‐paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large‐clone T cells are critical effectors in the antitumor response. This study also revealed tumor‐specific germinal center B cells associated with tertiary lymphoid structures. A high‐germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune‐excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy. Synopsis: Single‐cell level evaluation of the composition of malignant, immune, and stromal cells in the tumor microenvironment of cervical cancer (CC) determines critical subsets of immune response and prognosis.Single‐cell and immune repertoire analysis of CC and adjacent normal tissue highlights critical immune and stromal clusters.T cells are mostly exhausted in CC, while large clones are more prone to cytotoxic immune responses.The presence of tertiary lymphoid structures and germinal center response in CC tumors links to B‐cell–mediated anti‐tumor response.Co‐occurrence analysis of epithelial and stromal subsets provides a promising prognostic model for patients with CC. [ABSTRACT FROM AUTHOR]

As crucial epigenetic regulators, long noncoding RNAs (lncRNAs) play critical functions in development processes and various diseases. However, the regulatory mechanism of lncRNAs in early heart development is still limited. In this study, we identified cardiac mesoderm-related lncRNA (LncCMRR). Knockout (KO) of LncCMRR decreased the formation potential of cardiac mesoderm and cardiomyocytes during embryoid body differentiation of mouse embryonic stem (ES) cells. Mechanistic analyses showed that LncCMRR functionally interacted with the transcription suppressor PURB and inhibited its binding potential at the promoter region of Flk1, which safeguarded the transcription of Flk1 during cardiac mesoderm formation. We also carried out gene ontology term and signaling pathway enrichment analyses for the differentially expressed genes after KO of LncCMRR, and found significant correlation of LncCMRR with cardiac muscle contraction, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Consistently, the expression level of Flk1 at E7.75 and the thickness of myocardium at E17.5 were significantly decreased after KO of LncCMRR, and the survival rate and heart function index of LncCMRR-KO mice were also significantly decreased as compared with the wild-type group. These findings indicated that the defects in early heart development led to functional abnormalities in adulthood heart of LncCMRR-KO mice. Conclusively, our findings elucidate the main function and regulatory mechanism of LncCMRR in cardiac mesoderm formation, and provide new insights into lncRNA-mediated regulatory network of mouse ES cell differentiation. Graphical Abstract [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.08.038 Byline: Rui Yue (1), Jiuhong Kang (1)(2), Cong Zhao (1), Wenxiang Hu (1), Yawei Tang (1), Xiaosong Liu (1), Gang Pei (1)(2) Keywords: DEVBIO; DNA; PROTEINS Abstract: [beta]-Arrestin1 is a multifunctional protein critically involved in signal transduction. Recently, it is also identified as a nuclear transcriptional regulator, but the underlying mechanisms and physiological significance remain to be explored. Here, we identified [beta]-arrestin1 as an evolutionarily conserved protein essential for zebrafish development. Zebrafish embryos depleted of [beta]-arrestin1 displayed severe posterior defects and especially failed to undergo hematopoiesis. In addition, the expression of cdx4, a critical regulator of embryonic blood formation, and its downstream hox genes were downregulated by depletion of [beta]-arrestin1, while injection of cdx4, hoxa9a or hoxb4a mRNA rescued the hematopoietic defects. Further mechanistic studies revealed that [beta]-arrestin1 bound to and sequestered the polycomb group (PcG) recruiter YY1, and relieved PcG-mediated repression of cdx4-hox pathway, thus regulating hematopoietic lineage specification. Taken together, this study demonstrated a critical role of [beta]-arrestin1 during zebrafish primitive hematopoiesis, as well as an important regulator of PcG proteins and cdx4-hox pathway. Author Affiliation: (1) Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences; Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China (2) School of Life Science and Technology, Tongji University, 200092, Shanghai, China Article History: Received 15 January 2009; Revised 4 May 2009; Accepted 21 August 2009 Article Note: (miscellaneous) Published: October 29, 2009

Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling (1,2), which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins (3), leading to activation of the phosphatidylinositol-3-OH kinase (PI(3)K)-Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin (4-6). β-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals (7-11). Here we show that in diabetic mouse models, β-arrestin-2 is severely down-regulated. Knockdown of β-arrestin-2 exacerbates insulin resistance, whereas administration of β-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new β-arrestin-2 signal complex, in which β-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of β-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes. Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes., We first investigated the expression pattern of β-arrestins in the db/db mouse model of type 2 diabetes. There was a decrease in β-arrestin-2 protein and messenger RNA levels in liver [...]

Long noncoding RNAs (lncRNAs) are abundantly expressed in the nervous system, but their regulatory roles in neuronal differentiation are poorly understood. Using a human embryonic stem cell (hESC)‐based 2D neural differentiation approach and a 3D cerebral organoid system, we show that SOX1‐OT variant 1 (SOX1‐OT V1), a SOX1 overlapping noncoding RNA, plays essential roles in both dorsal cortical neuron differentiation and ventral GABAergic neuron differentiation by facilitating SOX1 expression. SOX1‐OT V1 physically interacts with HDAC10 through its 5' region, acts as a decoy to block HDAC10 binding to the SOX1 promoter, and thus maintains histone acetylation levels at the SOX1 promoter. SOX1 in turn activates ASCL1 expression and promotes neuronal differentiation. Taken together, we identify a SOX1‐OT V1/HDAC10‐SOX1‐ASCL1 axis, which promotes neurogenesis, highlighting a role for lncRNAs in hESC neuronal differentiation. Synopsis: SOX1‐OT V1 interacts with HDAC10 and blocks its binding to the SOX1 promoter, maintaining histone acetylation levels at the promoter to facilitate SOX1 expression. SOX1 in turn activates ASCL1 expression to promote dorsal cortical neuron and ventral GABAergic neuron differentiation. SOX1‐OT V1 promotes histone acetylation at the SOX1 promoter.SOX1‐OT V1 acts as a decoy of HDAC10 to block HDAC10 binding to the SOX1 promoterSOX1 directly activates ASCL1 to promote hESC neuronal differentiation [ABSTRACT FROM AUTHOR]