1,721,020 research outputs found
m6A RNA methylation and beyond - the epigenetic machinery and potential treatment options
Full text linkm6A is emerging as one of the most important RNA modifications because of its involvement in pathological and physiological events. Here, we provide an overview of this epitranscriptomic modification, beginning with a description of the molecular players involved and continuing with a focus on the role of m6A in the maintenance of stemness, induction of the epithelial to mesenchymal transition (EMT), and tumor progression. Finally, we discuss the state of the art regarding the design and validation of inhibitors of m6A writers or erasers to provide a background for future investigations and for the development of specific therapeutics
MyoD-Induced Trans-Differentiation: A Paradigm for Dissecting the Molecular Mechanisms of Cell Commitment, Differentiation and Reprogramming
No full textThe discovery of the skeletal muscle-specific transcription factor MyoD represents a milestone in the field of transcriptional regulation during differentiation and cell-fate reprogramming. MyoD was the first tissue-specific factor found capable of converting non-muscle somatic cells into skeletal muscle cells. A unique feature of MyoD, with respect to other lineage-specific factors able to drive trans-differentiation processes, is its ability to dramatically change the cell fate even when expressed alone. The present review will outline the molecular strategies by which MyoD reprograms the transcriptional regulation of the cell of origin during the myogenic conversion, focusing on the activation and coordination of a complex network of co-factors and epigenetic mechanisms. Some molecular roadblocks, found to restrain MyoD-dependent trans-differentiation, and the possible ways for overcoming these barriers, will also be discussed. Indeed, they are of critical importance not only to expand our knowledge of basic muscle biology but also to improve the generation skeletal muscle cells for translational research
Targeting of polycombs to DNA in EMT
Full text linkWe here describe the conceptual advance provided by the study by Battistelli and coworkers (PMID: 27452518), that shed light on a molecular mechanism of Polycomb targeting in the biological process known as Epithelial-to-Mesenchymal Transition (EMT).
In this paper, different working hypotheses of how EZH2 gets to its genomic targets have been reconciled and a new paradigm of function for a lncRNA is highlighted.
The interest may also arise from the clarification of the role of a lncRNA as a new molecular player in EMT regulation. This evidence holds promise for the development of novel therapeutic targets in carcinoma progression
Next RNA Therapeutics: The Mine of Non-Coding
No full textThe growing knowledge on several classes of non-coding RNAs (ncRNAs) and their different functional roles has aroused great interest in the scientific community. Beyond the Central Dogma of Biology, it is clearly known that not all RNAs code for protein products, and they exert a broader repertoire of biological functions. As described in this review, ncRNAs participate in gene expression regulation both at transcriptional and post-transcriptional levels and represent critical elements driving and controlling pathophysiological processes in multicellular organisms. For this reason, in recent years, a great boost was given to ncRNA-based strategies with potential therapeutic abilities, and nowadays, the use of RNA molecules is experimentally validated and actually exploited in clinics to counteract several diseases. In this review, we summarize the principal classes of therapeutic ncRNA molecules that are potentially implied in disease onset and progression, which are already used in clinics or under clinical trials, highlighting the advantages and the need for a targeted therapeutic strategy design. Furthermore, we discuss the benefits and the limits of RNA therapeutics and the ongoing development of delivery strategies to limit the off-target effects and to increase the translational application
A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells
Full text linkThe cdk inhibitor p57kip2, encoded by the Cdkn1c gene, plays a critical role in mammalian development and in the differentiation of several tissues. Cdkn1c protein levels are carefully regulated via imprinting and other epigenetic mechanisms affecting both the promoter and distant regulatory elements, which restrict its expression to particular developmental phases or specific cell types. Inappropriate activation of these regulatory mechanisms leads to Cdkn1c silencing, causing growth disorders and cancer. We have previously reported that, in skeletal muscle cells, induction of Cdkn1c expression requires the binding of the bHLH myogenic factor MyoD to a long-distance regulatory element within the imprinting control region KvDMR1. Interestingly, MyoD binding to KvDMR1 is prevented in myogenic cell types refractory to the induction of Cdkn1c. In the present work, we took advantage of this model system to investigate the epigenetic determinants of the differential interaction of MyoD with KvDMR1. We show that treatment with the DNA demethylating agent 5-azacytidine restores the binding of MyoD to KvDMR1 in cells unresponsive to Cdkn1c induction. This, in turn, promotes the release of a repressive chromatin loop between KvDMR1 and Cdkn1c promoter and, thus, the upregulation of the gene. Analysis of the chromatin status of Cdkn1c promoter and KvDMR1 in unresponsive compared to responsive cell types showed that their differential responsiveness to the MyoD-dependent induction of the gene does not involve just their methylation status but, rather, the differential H3 lysine 9 dimethylation at KvDMR1. Finally, we report that the same histone modification also marks the KvDMR1 region of human cancer cells in which Cdkn1c is silenced. On the basis of these results, we suggest that the epigenetic status of KvDMR1 represents a critical determinant of the cell type-restricted expression of Cdkn1c and, possibly, of its aberrant silencing in some pathological conditions
A lncRNA-mediated interaction between Snail and Ezh2 governs epigenetic modifications causal to EMT of the hepatocyte
No full textA lncRNA-mediated interaction between Snail and Ezh2 governs epigenetic modifications causal to EMT of the hepatocyte
Cecilia Battistelli1, Carla Cicchini1, Laura Santangelo1, Anna Tramontano2, Laura Amicone1 and Marco Tripodi1
1Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy
2Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Physics, Sapienza University of Rome, Rome, Italy
Co-authors
Epithelial-to-Mesenchymal Transition (EMT) and the reverse Mesenchymal-to-Epithelial Transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. We previously demonstrated that the balance between two transcriptional factors, Snail (EMT “master factor) and HNF4α (MET “master” factor), able to reciprocally repress their own expression, ultimately influences the outcome of the transition between the mesenchymal/ undifferentiated and the epithelial/differentiated phenotype. This necessarily implies that these master factors act in a much more complex macromolecular systems, able to direct and modulate a whole transcriptional profile. Starting from the working hypothesis that a transcriptional factor sufficient to trigger and drive EMT might be endowed with the capacity to locally impact chromatin modifications causal to its repressive role, we investigated on how chromatin modifiers instrumental to Snail repressive activity are recruited to its specific sites. We found that a long non-coding RNA mediates a physical interaction between Snail and EZH2, enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) and the main writer of chromatin repressive marks and demonstrated that a tripartite Snail/lncRNA/EZH2 complex is causal for the execution of a full EMT of hepatocytes.
2006-Cicchini C, et al. J Cell Physiol. Oct; 209(1):230-8.
2011- Santangelo L, et al. Hepatology Jun;53(6):2063-74
2012-Garibaldi F, et al Cell Death and Differentiation. Jun;19(6):937-46.
2015-Cicchini C, et al. Liver Int. Apr 25. doi: 10.1111/liv.12577.
2015-Cicchini C, et al. BBA GRM Volume 1849, Issue 8, August, Pages 919–929
Poly(ADP-ribose) Polymerase 1 (PARP1) restrains MyoD-dependent gene expression during muscle differentiation
Full text linkThe myogenic factor MyoD regulates skeletal muscle differentiation by interacting with a variety of chromatin-modifying complexes. Although MyoD can induce and maintain chromatin accessibility at its target genes, its binding and trans-activation ability can be limited by some types of not fully characterized epigenetic constraints. In this work we analysed the role of PARP1 in regulating MyoD-dependent gene expression. PARP1 is a chromatin-associated enzyme, playing a well recognized role in DNA repair and that is implicated in transcriptional regulation. PARP1 affects gene expression through multiple mechanisms, often involving the Poly(ADP-ribosyl)ation of chromatin proteins. In line with PARP1 down-regulation during differentiation, we observed that PARP1 depletion boosts the up-regulation of MyoD targets, such as p57, myogenin, Mef2C and p21, while its re-expression reverts this effect. We also found that PARP1 interacts with some MyoD-binding regions and that its presence, independently of the enzymatic activity, interferes with MyoD recruitment and gene induction. We finally suggest a relationship between the binding of PARP1 and the loss of the activating histone modification H3K4me3 at MyoD-binding regions. This work highlights not only a novel player in the epigenetic control of myogenesis, but also a repressive and catalytic-independent mechanisms by which PARP1 regulates transcription
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