MicroRNA Control of TGF-β Signaling Suzuki, Hiroshi I
International journal of molecular sciences,
07/2018, Volume:
19, Issue:
7
Journal Article
Peer reviewed
Open access
Transcriptional and post-transcriptional regulation shapes the transcriptome and proteome changes induced by various cellular signaling cascades. MicroRNAs (miRNAs) are small regulatory RNAs that are ...approximately 22 nucleotides long, which direct the post-transcriptional regulation of diverse target genes and control cell states. Transforming growth factor (TGF)-β family is a multifunctional cytokine family, which plays many regulatory roles in the development and pathogenesis of diverse diseases, including fibrotic disease, cardiovascular disease and cancer. Previous studies have shown that the TGF-β pathway includes the miRNA pathway as an important component of its downstream signaling cascades. Multiple studies of epithelial⁻mesenchymal transition (EMT)-related miRNAs have highlighted that miRNAs constitute the intrinsic bistable molecular switches of cell states by forming double negative feedback loops with EMT-inducing transcription factors. This may be important for understanding the reversibility of EMT at the single-cell level, the presence of distinct EMT transition states and the intra- and inter-tumor heterogeneity of cancer cell phenotypes. In the present review, I summarize the connection between TGF-β signaling and the miRNA pathway, placing particular emphasis on the regulation of miRNA expression by TGF-β signaling, the modulation of TGF-β signaling by miRNAs, the miRNA-mediated modulation of EMT and endothelial⁻mesenchymal transition as well as the crosstalk between miRNA and TGF-β pathways in the tumor microenvironment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging ...pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer's disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the ...transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA-target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Understanding the characteristics of cancer cells is essential for the development of improved diagnosis and therapeutics. From a gene regulation perspective, the super‐enhancer concept has been ...introduced to systematically understand the molecular mechanisms underlying the identities of various cell types and has been extended to the analysis of cancer cells and cancer genome alterations. In addition, several characteristic features of super‐enhancers have led to the recognition of the link between gene regulation and biomolecular condensates, which is often mediated by liquid‐liquid phase separation. Several lines of evidence have suggested molecular and biophysical principles and their alterations in cancer cells, which are particularly associated with gene regulation and cell signaling (“ transcriptional” and “signaling” condensates). These findings collectively suggest that the modification of biomolecular condensates represents an important mechanism by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression. The condensate model also provides the molecular basis of the vulnerability of cancer cells to transcriptional perturbation and further suggests the possibility of therapeutic targeting of condensates. This review summarizes recent findings regarding the relationships between super‐enhancers and biomolecular condensate models, multiple scenarios of condensate alterations in cancers, and the potential of the condensate model for therapeutic development.
In this review, we summarize recent findings regarding the relationships between super‐enhancers and the biomolecular condensates, multiple scenarios of condensate alterations in cancer, and the potentials of the condensate model for therapeutic development. Modification of biomolecular condensates may be important mechanisms by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In 1973, rotaviruses A (RVAs) were discovered as major causative agents of acute gastroenteritis in infants and young children worldwide. The infectious RV virion is an icosahedral particle composed ...of three concentric protein layers surrounding the 11 double-stranded (dsRNA) segments. An in vitro replication system for RVs in permanent cell lines was developed in 1982 and expanded to replication in intestinal organoids in 2015. However, the details of rotavirus (RV) entry into cells and particle maturation mechanisms at the molecular level remain incompletely understood. Slowing down human RVA replication in cell culture on ice allowed morphological visualization of virus particle entry and the assembly of triple-layered particles (virion). Although RVAs are non-enveloped viruses, after virus attachment to the cell membrane, the virus enters the cell by perforating the plasma membrane by a fusion mechanism involving VP5* of the cleaved VP4 protein, as the alternative virus entry route besides the receptor-mediated endocytosis which is generally accepted. After assembling double-layered particles (DLPs) in viroplasm or cytoplasm, they appear to be connected with the endoplasmic reticulum (ER) membrane and become coated with outer capsid proteins (VP4 and VP7) in a coating process. The perforation of the ER membrane is caused by an unknown mechanism following interaction between non-structural protein 4 (NSP4) and the inner capsid protein VP6 of the DLPs. The coating process is closely related to the formation of a hetero-oligomeric complex (NSP4, VP4 and VP7). These lines of evidence suggest the existence of novel mechanisms of RV morphogenesis.
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we ...report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.
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•Super-enhancers and broad H3K4me3 domains shape miRNA expression atlas•Super-enhancer constituents act together and boost pri-miRNA processing•Brd4 inhibition inhibits chromatin DGCR8/Drosha recruitment and miRNA processing•Alterations of super-enhancers for multiple cancer-related miRNAs
Super-enhancers recruit components of the miRNA-processing machinery to influence its processing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is ...dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies ...have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter‐individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network‐defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete‐scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.
Subtypes of SCLC cell lines defined by expression patterns of transcription factors. Two‐dimensional hierarchical clustering of expression levels of 1520 transcription factors in SCLC cell lines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour ...suppressors and oncogenes in tumour development, a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis. This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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