Integration of Transcriptome and Methylome Highlights the Roles of Cell Cycle and Hippo Signaling Pathway in Flatfish Sexual Size Dimorphism

Sexual size dimorphism (SSD) is the difference in segments or body size between sexes prevalent in various species. Understanding the genetic architecture of SSD has remained a significant challenge owing to the complexity of growth mechanisms and the sexual influences among species. The Chinese tongue sole (Cynoglossus semilaevis), which exhibits a female-biased SSD and sex reversal from female to pseudomale, is an ideal model for exploring SSD mechanism at the molecular level. The present study aimed to integrate transcriptome and methylome analysis to unravel the genetic and epigenetic changes in female, male, and pseudomale C. semilaevis. The somatotropic and reproductive tissues (brain, liver, gonad, and muscle) transcriptomes were characterized by RNA-seq technology. Transcriptomic analysis unravelled numerous differentially expressed genes (DEGs) involved in cell growth and death-related pathways. The gonad and muscle methylomes were further employed for screening differentially methylated genes (DMGs). Relatively higher DNA methylation levels were observed in the male and pseudomale individuals. In detail, hypermethylation of the chromosome W was pronounced in the pseudomale group than in the female group. Furthermore, weighted gene co-expression network analysis showed that turquoise and brown modules positively and negatively correlated with the female-biased SSD, respectively. A combined analysis of the module genes and DMGs revealed the female-biased mRNA transcripts and hypomethylated levels in the upstream and downstream regions across the cell cycle-related genes. Moreover, the male and pseudomale-biased gene expression in the hippo signaling pathway were positively correlated with their hypermethylation levels in the gene body. These findings implied that the activation of the cell cycle and the inhibition of the hippo signaling pathway were implicated in C. semilaevis female-biased SSD. In addition, the dynamic expression pattern of the epigenetic regulatory factors, including dnmt1, dnmt3a, dnmt3b, and uhrf1, among the different sexes correspond with their distinct DNA methylation levels. Herein, we provide valuable clues for understanding female-biased SSD in C. semilaevis.

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ANKHD1, a novel component of the Hippo signaling pathway, promotes YAP1 activation and cell cycle progression in prostate cancer cells

Experimental Cell Research ◽

10.1016/j.yexcr.2014.04.004 ◽

2014 ◽

Vol 324 (2) ◽

pp. 137-145 ◽

Cited By ~ 34

Author(s):

João Agostinho Machado-Neto ◽

Mariana Lazarini ◽

Patricia Favaro ◽

Gilberto Carlos Franchi ◽

Alexandre Eduardo Nowill ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Signaling Pathway ◽

Cell Cycle Progression ◽

Hippo Signaling ◽

Prostate Cancer Cells ◽

Cycle Progression ◽

Hippo Signaling Pathway

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Zika virus alters DNA methylation status of genes involved in Hippo signaling pathway in human neural progenitor cells

Epigenomics ◽

10.2217/epi-2018-0180 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1143-1161 ◽

Cited By ~ 5

Author(s):

Deepika Kandilya ◽

Silambarasan Maskomani ◽

Sukanya Shyamasundar ◽

Paul Anantharajah Tambyah ◽

Chan Shiao Yng ◽

...

Keyword(s):

Dna Methylation ◽

Progenitor Cells ◽

Signaling Pathway ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Methylation Status ◽

Neural Progenitor ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Human Neural Progenitor Cells

Aim: This study was aimed to understand if Zika virus (ZIKV) alters the DNA methylome of human neural progenitor cells (hNPCs). Materials & methods: Whole genome DNA methylation profiling was performed using human methylationEPIC array in control and ZIKV infected hNPCs. Results & conclusion: ZIKV infection altered the DNA methylation of several genes such as WWTR1 (TAZ) and RASSF1 of Hippo signaling pathway which regulates organ size during brain development, and decreased the expression of several centrosomal-related microcephaly genes, and genes involved in stemness and differentiation in human neural progenitor cells. Overall, ZIKV downregulated the Hippo signaling pathway genes which perturb the stemness and differentiation process in hNPCs, which could form the basis for ZIKV-induced microcephaly.

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Overexpression of Agrin promotes tumor proliferation and correlates with poor prognosis in cholangiocarcinoma

10.21203/rs.3.rs-50004/v1 ◽

2020 ◽

Author(s):

Meimei He ◽

Shasha Ji ◽

Junxue Tu ◽

Dan Lou

Keyword(s):

Cell Cycle ◽

Signaling Pathway ◽

Cell Lines ◽

Target Genes ◽

Intrahepatic Metastasis ◽

Control Group ◽

Hippo Signaling ◽

Tumor Characteristics ◽

Hippo Signaling Pathway

Abstract Background Agrin exists as a shorter Type II Transmembrane form with an internal signal peptide, and is closely correlated with the activation of multiple intercellular signaling pathways. The aim of the present study was to investigate the role of Agrin in the development of cholangiocarcinoma (CCA). Methods RT-qPCR and western blotting were performed to detect the expressional level of target genes, including Agrin, in CCA tissues or cell lines. The correlation between Agrin, and tumor characteristics and prognosis, was analyzed using independent sample t-test, the Kaplan-Meier method and Cox proportional hazard model, respectively. Proliferation, migration, invasion and tumorigenesis in CCA cells was determined by CCK8 assay, cell cycle detection, Transwell assay and nude mouse tumorigenicity assay, respectively. Results Agrin was significantly upregulated in CCA tissues, as compared to the adjacent non-tumor tissues, and was correlated with poorer tumor characteristics such as portal vein tumor thrombus, intrahepatic metastasis and poor survival. The Agrin overexpression in CCA cell lines clearly promoted proliferation, colony formation, migration, invasion and cell cycle progression, but Agrin knockdown had the opposite effect. Furthermore, CCA cells with inhibitory Agrin expression presented with less and smaller tumors, as compared with the control group in vivo. Mechanistic analysis indicated that Agrin was able to activate the Hippo signaling pathway and induce yap to enter the cell nucleus. Conclusions We found that Agrin promotes the CCA progression via activating the Hippo signaling pathway, which could be a potentially promising target for CCA treatment.

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Nitidine chloride possesses anticancer property in lung cancer cells through activating Hippo signaling pathway

Cell Death Discovery ◽

10.1038/s41420-020-00326-7 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Jing Zhang ◽

Linhui Wu ◽

Chaoqun Lian ◽

Shuo Lian ◽

Shimeng Bao ◽

...

Keyword(s):

Cell Cycle ◽

Western Blot ◽

Signaling Pathway ◽

Migration And Invasion ◽

Hippo Signaling ◽

Protein Expression Level ◽

Hippo Signaling Pathway ◽

Proliferation Ability ◽

And Migration ◽

Western Blot Data

Abstract Nitidine chloride (NC) has significant anti-tumor properties; however, the precise mechanism related to NC still needs further investigation. This study intends to investigate the anti-tumor functions and the feasible molecular basis of NC in NSCLC cells. Therefore, we determined the mechanism of NC-mediated anti-tumor function through various methods. Cell proliferation ability and migration and invasion were detected by CCK-8, colony formation assay and Transwell assay, respectively. Furthermore, flow cytometry was used to detect apoptosis, cell cycle and ROS. Moreover, protein expression level was measured by western blot. Our results showed that NC can inhibit the growth, motility of NSCLC cells, induce apoptosis and arrest cell cycle. Meanwhile, NC increased the level of ROS in NSCLC cells. Moreover, western blot data showed that NC suppressed the expression of Lats1, Mob1, and YAP, and enhanced the expression of p-Lats1, p-Mob1, p-YAP1 (ser127). Overall, our research reveals that NC exerts anticancer activity by activating and modulating the Hippo signaling pathway.

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Hippo signaling pathway in mammals：a new therapeutic target for tumors

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2012.00269 ◽

2012 ◽

Vol 34 (3) ◽

pp. 269-280 ◽

Cited By ~ 2

Author(s):

Chuan-Ming XU ◽

Fu-Sheng WAN

Keyword(s):

Signaling Pathway ◽

Therapeutic Target ◽

Hippo Signaling ◽

Hippo Signaling Pathway

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Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01830-z ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xuehui Wang ◽

Changle Ji ◽

Jiashu Hu ◽

Xiaochong Deng ◽

Wenfang Zheng ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Cell Lines ◽

Luciferase Reporter ◽

Circular Rnas ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Potential Biomarker

Abstract Background Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1. Results Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.

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Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms22020931 ◽

2021 ◽

Vol 22 (2) ◽

pp. 931

Author(s):

Jihyun Lee ◽

Yujin Jung ◽

Seo won Jeong ◽

Ga Hee Jeong ◽

Gue Tae Moon ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Normal Skin ◽

Skin Lesions ◽

Hippo Signaling ◽

Vascular Endothelial ◽

Expression Levels ◽

Hippo Signaling Pathway ◽

Endothelial Growth Factor

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

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