Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) in carcinoma cells. EMT not only ...plays an important role in embryonic development and malignant progression, but is also implicated in cancer therapy resistance. It has been hypothesized that carcinoma cells that have undergone EMT acquire cancer stem cell properties including self-renewal, chemoresistance and radioresistance. However, our recent data indicate that ZEB1 regulates radioresistance in breast cancer cells through an EMT-independent mechanism. In this Perspective, we review different mechanisms by which ZEB1 regulates tumor progression and treatment resistance. Based on studies by us and others, we propose that it is specific EMT inducers like ZEB1, but not the epithelial or mesenchymal state itself, that dictate cancer stem cell properties.
Non-Coding RNAs and their Integrated Networks Zhang, Peijing; Wu, Wenyi; Chen, Qi ...
Berichte aus der medizinischen Informatik und Bioinformatik/Journal of integrative bioinformatics,
07/2019, Volume:
16, Issue:
3
Journal Article
Peer reviewed
Open access
Eukaryotic genomes are pervasively transcribed. Besides protein-coding RNAs, there are different types of non-coding RNAs that modulate complex molecular and cellular processes. RNA sequencing ...technologies and bioinformatics methods greatly promoted the study of ncRNAs, which revealed ncRNAs’ essential roles in diverse aspects of biological functions. As important key players in gene regulatory networks, ncRNAs work with other biomolecules, including coding and non-coding RNAs, DNAs and proteins. In this review, we discuss the distinct types of ncRNAs, including housekeeping ncRNAs and regulatory ncRNAs, their versatile functions and interactions, transcription, translation, and modification. Moreover, we summarize the integrated networks of ncRNA interactions, providing a comprehensive landscape of ncRNAs regulatory roles.
Leaf development is a complex biological process that is accompanied by wide transcriptional changes. Many protein-coding genes have been characterized in plant leaves, but little attention has been ...given to noncoding RNAs (ncRNAs). Moreover, increasing evidence indicates that an intricate interplay among RNA species, including protein-coding RNAs and ncRNAs, exists in eukaryotic transcriptomes, however, it remains elusive in plant leaves.
We detected novel ncRNAs, such as circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs), and further constructed and analyzed their associated competitive endogenous RNA (ceRNA) networks in Arabidopsis leaves. Transcriptome profiling showed extensive changes during leaf development. In addition, comprehensive detection of circRNAs in other plant leaves suggested that circRNAs are widespread in plant leaves. To investigate the complex post-transcriptional interactions in Arabidopsis leaves, we constructed a global circRNA/lncRNA-associated ceRNA network. Functional analysis revealed that ceRNAs were highly correlated with leaf development. These ceRNAs could be divided into six clusters, which were enriched for different functional classes. Stage-specific ceRNA networks were further constructed and comparative analysis revealed different roles of stage common and specific hub ceRNAs.
Our results demonstrate that understanding the ceRNA interactions will lead insights into gene regulations implicated in leaf development.
Long non-coding RNAs （lncRNAs） have gained massive attention in recent years as a potentially new and crucial layer of gene regulation. LncRNAs are prevalently transcribed in the genome, but their ...roles in gene regulation and disease development are largely unknown. HOX antisense intergenic RNA （HOTAIR）, a lncRNA located in the HOXC locus, has been shown to repress HOXD gene expression and promote breast cancer metastasis. Mechanistically, HOTAIR interacts with and recruits polycomb repressive complex 2 （PRC2） and regulates chromosome occupancy by EZH2 （a subunit of PRC2）, which leads to histone H3 lysine 27 trimethylation of the HOXD locus. Moreover, HOTAIR is pervasively overexpressed in most human cancers compared with noncancerous adjacent tissues. This review summarizes the studies on the HOTAIR lncRNA over the past 6 years.
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or ...specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.
Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic ...retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCF
E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function. Independently of Hippo signaling, mutation of YAP's K63-linkage specific ubiquitination sites K321 and K497, depletion of SKP2, or overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. Conversely, overexpression of SKP2 or loss of OTUD1 leads to nuclear localization and activation of YAP. Altogether, our study sheds light on the ubiquitination-mediated, Hippo-independent regulation of YAP.
CircRNAs are covalently closed-loop single-stranded RNA molecules ubiquitously expressing in eukaryotes. As an important member of the endogenous ncRNA family, circRNAs are associated with diverse ...biological processes and can regulate transcription, modulate alternative splicing, and interact with miRNAs or proteins. Compared to abundant advances in animals, studies of circRNAs in plants are rapidly emerging. The databases and analysis tools for plant circRNAs are constantly being developed. Large numbers of circRNAs have been identified and characterized in plants and proved to play regulatory roles in plant growth, development, and stress responses. Here, we review the biogenesis, characteristics, bioinformatics resources, and biological functions of plant circRNAs, and summarize the distinct circularization features and differentially expression patterns comparison with animal-related results.CircRNAs are covalently closed-loop single-stranded RNA molecules ubiquitously expressing in eukaryotes. As an important member of the endogenous ncRNA family, circRNAs are associated with diverse biological processes and can regulate transcription, modulate alternative splicing, and interact with miRNAs or proteins. Compared to abundant advances in animals, studies of circRNAs in plants are rapidly emerging. The databases and analysis tools for plant circRNAs are constantly being developed. Large numbers of circRNAs have been identified and characterized in plants and proved to play regulatory roles in plant growth, development, and stress responses. Here, we review the biogenesis, characteristics, bioinformatics resources, and biological functions of plant circRNAs, and summarize the distinct circularization features and differentially expression patterns comparison with animal-related results.
The tumour suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ...ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes the PTEN protein through direct binding and deubiquitylation of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumour growth through downregulation of PTEN. Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN-positive but not PTEN-null breast cancer cells. Importantly, USP13 protein is downregulated in human breast tumours and correlates with PTEN protein levels. These findings identify USP13 as a tumour-suppressing protein that functions through deubiquitylation and stabilization of PTEN.
Plant genomes encode a complex and evolutionary diverse regulatory grammar that forms the basis for most life on earth. A wealth of regulome and epigenome data have been generated in various plant ...species, but no common, standardized resource is available so far for biologists. Here, we present ChIP-Hub, an integrative web-based platform in the ENCODE standards that bundles >10,000 publicly available datasets reanalyzed from >40 plant species, allowing visualization and meta-analysis. We manually curate the datasets through assessing ~540 original publications and comprehensively evaluate their data quality. As a proof of concept, we extensively survey the co-association of different regulators and construct a hierarchical regulatory network under a broad developmental context. Furthermore, we show how our annotation allows to investigate the dynamic activity of tissue-specific regulatory elements (promoters and enhancers) and their underlying sequence grammar. Finally, we analyze the function and conservation of tissue-specific promoters, enhancers and chromatin states using comparative genomics approaches. Taken together, the ChIP-Hub platform and the analysis results provide rich resources for deep exploration of plant ENCODE. ChIP-Hub is available at https://biobigdata.nju.edu.cn/ChIPHub/ .
Plant transcriptomes encompass a large number of functional non-coding RNAs (ncRNAs), only some of which have protein-coding capacity. Since their initial discovery, ncRNAs have been classified into ...two broad categories based on their biogenesis and mechanisms of action, housekeeping ncRNAs and regulatory ncRNAs. With advances in RNA sequencing technology and computational methods, bioinformatics resources continue to emerge and update rapidly, including workflow for in silico ncRNA analysis, up-to-date platforms, databases, and tools dedicated to ncRNA identification and functional annotation. In this review, we aim to describe the biogenesis, biological functions, and interactions with DNA, RNA, protein, and microorganism of five major regulatory ncRNAs (miRNA, siRNA, tsRNA, circRNA, lncRNA) in plants. Then, we systematically summarize tools for analysis and prediction of plant ncRNAs, as well as databases. Furthermore, we discuss the silico analysis process of these ncRNAs and present a protocol for step-by-step computational analysis of ncRNAs. In general, this review will help researchers better understand the world of ncRNAs at multiple levels.
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