scholarly journals The METTL3-m6A Epitranscriptome: Dynamic Regulator of Epithelial Development, Differentiation, and Cancer

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1019
Author(s):  
Alexandra Maldonado López ◽  
Brian C. Capell
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Squamous Cell Carcinomas ◽  
Fine Tuning ◽  
Epigenetic Mechanisms ◽  
Control Of Gene Expression ◽  
Epithelial Development ◽  
Targeted Inhibitors

Dynamic modifications on RNA, frequently termed both, “RNA epigenetics” and “epitranscriptomics”, offer one of the most exciting emerging areas of gene regulation and biomedicine. Similar to chromatin-based epigenetic mechanisms, writers, readers, and erasers regulate both the presence and interpretation of these modifications, thereby adding further nuance to the control of gene expression. In particular, the most abundant modification on mRNAs, N6-methyladenosine (m6A), catalyzed by methyltransferase-like 3 (METTL3) has been shown to play a critical role in self-renewing somatic epithelia, fine-tuning the balance between development, differentiation, and cancer, particularly in the case of squamous cell carcinomas (SCCs), which in aggregate, outnumber all other human cancers. Along with the development of targeted inhibitors of epitranscriptomic modulators (e.g., METTL3) now entering clinical trials, the field holds significant promise for treating these abundant cancers. Here, we present the most current summary of this work, while also highlighting the therapeutic potential of these discoveries.

A Review on Important Histone Acetyltransferase (HAT) Enzymes as Targets for Cancer Therapy

2019 ◽  
Vol 15 (2) ◽  
pp. 120-130
Author(s):  
Mohammad Ghanbari ◽  
Reza Safaralizadeh ◽  
Kiyanoush Mohammadi
Keyword(s):  
Gene Expression ◽  
Histone Acetyltransferase ◽  
Critical Role ◽  
Cancer Treatments ◽  
Control Of Gene Expression ◽  
Post Translational Modifications ◽  
Therapeutic Drugs ◽  
The Status ◽  
Acetyl Group ◽  
Increase Gene Expression

At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.

scholarly journals Leveraging epigenetics to enhance the efficacy of immunotherapy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jonathan D. Licht ◽  
Richard L. Bennett
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Antigen Presentation ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Epigenetic Modifications ◽  
Main Body ◽  
Epigenetic Mechanisms

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

Epigenetics

2019 ◽  
pp. 56-70
Author(s):  
Edward Hookway ◽  
Nicholas Athanasou ◽  
Udo Oppermann
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tumour Suppressor Genes ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

scholarly journals Chromatin-associated protein complexes link DNA base J and transcription termination in Leishmania

2020 ◽  
Author(s):  
Bryan C Jensen ◽  
Isabelle Q. Phan ◽  
Jacquelyn R. McDonald ◽  
Aakash Sur ◽  
Mark A. Gillespie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Protein Complexes ◽  
Transcription Termination ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Control Of Gene Expression ◽  
Polycistronic Transcription ◽  
Post Transcriptional Regulation

AbstractUnlike most other eukaryotes, Leishmania and other trypanosomatid protozoa have largely eschewed transcriptional control of gene expression; relying instead on post-transcriptional regulation of mRNAs derived from polycistronic transcription units (PTUs). In these parasites, a novel modified nucleotide base (β-D-glucopyranosyloxymethyluracil) known as J plays a critical role in ensuring that transcription termination occurs only at the end of each PTU, rather than at the polyadenylation sites of individual genes. To further understand the biology of J-associated processes, we used tandem affinity purification (TAP-tagging) and mass spectrometry to reveal proteins that interact with the glucosyltransferase performing the final step in J synthesis. These studies identified four proteins reminiscent of subunits in the PTW/PP1 complex that controls transcription termination in higher eukaryotes. Moreover, bioinformatic analyses identified the DNA-binding subunit of Leishmania PTW/PP1 as a novel J-binding protein (JBP3). Down-regulation of JBP3 expression levels in Leishmania resulted in a substantial increase in transcriptional read-through at the 3’ end of most PTUs. Additional TAP-tagging experiments showed that JBP3 also associates with two other protein complexes. One consists of subunits with domains suggestive of a role in chromatin modification/remodeling; while the other contains subunits with similarity to those found in the PAF1 complex involved in regulation of transcription in other eukaryotes. Thus, trypanosomatids utilize protein complexes similar to those used to control transcription termination in other eukaryotes and JBP3 appears to function as a hub linking these modules to base J, thereby enabling the parasites’ unique reliance on polycistronic transcription and post-transcriptional regulation of gene expression.

Non-coding RNAs: what are we missing?

2020 ◽  
Vol 98 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Cristina Carvalho Barbosa ◽  
Sydnee H. Calhoun ◽  
Hans-Joachim Wieden
Keyword(s):  
Gene Expression ◽  
External Stress ◽  
Fine Tuning ◽  
Transcriptional Level ◽  
Control Of Gene Expression ◽  
Cell Responses ◽  
The Past ◽  
Domains Of Life ◽  
Non Coding Rnas

Over the past two decades, the importance of small non-coding RNAs (sncRNAs) as regulatory molecules has become apparent in all three domains of life (archaea, bacteria, eukaryotes). In fact, sncRNAs play an important role in the control of gene expression at both the transcriptional and the post-transcriptional level, with crucial roles in fine-tuning cell responses during internal and external stress. Multiple pathways for sncRNA biogenesis and diverse mechanisms of regulation have been reported, and although biogenesis and mechanisms of sncRNAs in prokaryotes and eukaryotes are different, remarkable similarities exist. Here, we briefly review and compare the major sncRNA classes that act post-transcriptionally, and focus on recent discoveries regarding the ribosome as a target of regulation and the conservation of these mechanisms between prokaryotes and eukaryotes.

scholarly journals The Critical Role of miRNAs in Regulation of Flowering Time and Flower Development

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 319
Author(s):  
Saquib Waheed ◽  
Lihui Zeng
Keyword(s):  
Gene Expression ◽  
Flower Development ◽  
Critical Role ◽  
Transcriptional Level ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Time Of Year ◽  
Acting In Concert ◽  
Flowering Process

Flowering is an important biological process for plants that ensures reproductive success. The onset of flowering needs to be coordinated with an appropriate time of year, which requires tight control of gene expression acting in concert to form a regulatory network. MicroRNAs (miRNAs) are non-coding RNAs known as master modulators of gene expression at the post-transcriptional level. Many different miRNA families are involved in flowering-related processes such as the induction of floral competence, floral patterning, and the development of floral organs. This review highlights the diverse roles of miRNAs in controlling the flowering process and flower development, in combination with potential biotechnological applications for miRNAs implicated in flower regulation.

scholarly journals Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2919-2928 ◽  
Author(s):  
Arturo Hernandez ◽  
Beatriz Morte ◽  
Mónica M. Belinchón ◽  
Ainhoa Ceballos ◽  
Juan Bernal
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Thyroid Hormone ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Control Of Gene Expression ◽  
High Doses ◽  
And Function ◽  
Type 3

Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T3 to nuclear receptors. Brain T3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T4 and T3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels.

scholarly journals Transcriptome-Wide Identification of Hfq-Associated RNAs in Brucella suis by Deep Sequencing

2015 ◽  
Vol 198 (3) ◽  
pp. 427-435 ◽  
Author(s):  
Bashir Saadeh ◽  
Clayton C. Caswell ◽  
Yanjie Chao ◽  
Philippe Berta ◽  
Alice Rebecca Wattam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Deep Sequencing ◽  
Noncoding Rnas ◽  
Northern Blotting ◽  
Fine Tuning ◽  
Sequencing Analysis ◽  
Control Of Gene Expression ◽  
Content Type ◽  
Small Noncoding Rnas ◽  
Brucella Suis

ABSTRACTRecent breakthroughs in next-generation sequencing technologies have led to the identification of small noncoding RNAs (sRNAs) as a new important class of regulatory molecules. In prokaryotes, sRNAs are often bound to the chaperone protein Hfq, which allows them to interact with their partner mRNA(s). We screened the genome of the zoonotic and human pathogenBrucella suis1330 for the presence of this class of RNAs. We designed a coimmunoprecipitation strategy that relies on the use of Hfq as a bait to enrich the sample with sRNAs and eventually their target mRNAs. By deep sequencing analysis of the Hfq-bound transcripts, we identified a number of mRNAs and 33 sRNA candidates associated with Hfq. The expression of 10 sRNAs in the early stationary growth phase was experimentally confirmed by Northern blotting and/or reverse transcriptase PCR.IMPORTANCEBrucellaorganisms are facultative intracellular pathogens that use stealth strategies to avoid host defenses. Adaptation to the host environment requires tight control of gene expression. Recently, small noncoding RNAs (sRNAs) and the sRNA chaperone Hfq have been shown to play a role in the fine-tuning of gene expression. Here we have used RNA sequencing to identify RNAs associated with theB. suisHfq protein. We have identified a novel list of 33 sRNAs and 62 Hfq-associated mRNAs for future studies aiming to understand the intracellular lifestyle of this pathogen.

scholarly journals The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Alejandra Monserrat Retis-Resendiz ◽  
Ixchel Nayeli González-García ◽  
Moisés León-Juárez ◽  
Ignacio Camacho-Arroyo ◽  
Marco Cerbón ◽  
...  
Keyword(s):  
Gene Expression ◽  
Menstrual Cycle ◽  
Fine Tuning ◽  
Cycle Phase ◽  
Transcriptional Networks ◽  
Epigenetic Mechanisms ◽  
Cell Type ◽  
Expression Of Genes ◽  
Non Coding Rnas

Abstract Background The human endometrium is a highly dynamic tissue whose function is mainly regulated by the ovarian steroid hormones estradiol and progesterone. The serum levels of these and other hormones are associated with three specific phases that compose the endometrial cycle: menstrual, proliferative, and secretory. Throughout this cycle, the endometrium exhibits different transcriptional networks according to the genes expressed in each phase. Epigenetic mechanisms are crucial in the fine-tuning of gene expression to generate such transcriptional networks. The present review aims to provide an overview of current research focused on the epigenetic mechanisms that regulate gene expression in the cyclical endometrium and discuss the technical and clinical perspectives regarding this topic. Main body The main epigenetic mechanisms reported are DNA methylation, histone post-translational modifications, and non-coding RNAs. These epigenetic mechanisms induce the expression of genes associated with transcriptional regulation, endometrial epithelial growth, angiogenesis, and stromal cell proliferation during the proliferative phase. During the secretory phase, epigenetic mechanisms promote the expression of genes associated with hormone response, insulin signaling, decidualization, and embryo implantation. Furthermore, the global content of specific epigenetic modifications and the gene expression of non-coding RNAs and epigenetic modifiers vary according to the menstrual cycle phase. In vitro and cell type-specific studies have demonstrated that epithelial and stromal cells undergo particular epigenetic changes that modulate their transcriptional networks to accomplish their function during decidualization and implantation. Conclusion and perspectives Epigenetic mechanisms are emerging as key players in regulating transcriptional networks associated with key processes and functions of the cyclical endometrium. Further studies using next-generation sequencing and single-cell technology are warranted to explore the role of other epigenetic mechanisms in each cell type that composes the endometrium throughout the menstrual cycle. The application of this knowledge will definitively provide essential information to understand the pathological mechanisms of endometrial diseases, such as endometriosis and endometrial cancer, and to identify potential therapeutic targets and improve women’s health.

DNA methylation and epigenetic inheritance

1990 ◽  
Vol 326 (1235) ◽  
pp. 329-338 ◽  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Germ Line ◽  
Experimental System ◽  
Epigenetic Inheritance ◽  
Epigenetic Mechanisms ◽  
Control Of Gene Expression ◽  
Developmental Programme

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

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