International Journal of Molecular Sciences

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19 pages, 6577 KiB

Open AccessArticle

The Distinct Function and Localization of METTL3/METTL14 and METTL16 Enzymes in Cardiomyocytes

by Orazio Angelo Arcidiacono, Jana Krejčí and Eva Bártová

Int. J. Mol. Sci. 2020, 21(21), 8139; https://doi.org/10.3390/ijms21218139 - 30 Oct 2020

Cited by 16 | Viewed by 4159

Abstract

It has become evident that epitranscriptome events, mediated by specific enzymes, regulate gene expression and, subsequently, cell differentiation processes. We show that methyltransferase-like proteins METTL3/METTL14 and N⁶-adenosine methylation (m6A) in RNAs are homogeneously distributed in embryonic hearts, and histone deacetylase (HDAC) [...] Read more.

It has become evident that epitranscriptome events, mediated by specific enzymes, regulate gene expression and, subsequently, cell differentiation processes. We show that methyltransferase-like proteins METTL3/METTL14 and N⁶-adenosine methylation (m6A) in RNAs are homogeneously distributed in embryonic hearts, and histone deacetylase (HDAC) inhibitors valproic acid and Trichostatin A (TSA) up-regulate METTL3/METTL14 proteins. The levels of METTL3 in mouse adult hearts, isolated from male and female animals, were lower in the aorta and pulmonary trunks when compared with atria, but METT14 was up-regulated in the aorta and pulmonary trunk, in comparison with ventriculi. Aging caused METTL3 down-regulation in aorta and atria in male animals. Western blot analysis in differentiated mouse embryonic stem cells (mESCs), containing 10–30 percent of cardiomyocytes, showed METTL3/METTL14 down-regulation, while the differentiation-induced increased level of METTL16 was observed in both wild type (wt) and HDAC1 depleted (dn) cells. In parallel, experimental differentiation in especially HDAC1 wild type cells was accompanied by depletion of m6A in RNA. Immunofluorescence analysis of individual cells revealed the highest density of METTL3/METTL14 in α-actinin positive cardiomyocytes when compared with the other cells in the culture undergoing differentiation. In both wt and HDAC1 dn cells, the amount of METTL16 was also up-regulated in cardiomyocytes when compared to co-cultivated cells. Together, we showed that distinct anatomical regions of the mouse adult hearts are characterized by different levels of METTL3 and METTL14 proteins, which are changed during aging. Experimental cell differentiation was also accompanied by changes in METTL-like proteins and m6A in RNA; in particular, levels and distribution patterns of METTL3/METTL14 proteins were different from the same parameters studied in the case of the METTL16 protein. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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21 pages, 17993 KiB

Open AccessArticle

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

by Annabelle Friedrich, Ann-Sophie Assmann, Lena Schumacher, Jana v. Stuijvenberg, Matthias U. Kassack, Wolfgang A. Schulz, Wynand P. Roos, Finn K. Hansen, Marc Pflieger, Thomas Kurz and Gerhard Fritz

Int. J. Mol. Sci. 2020, 21(13), 4747; https://doi.org/10.3390/ijms21134747 - 03 Jul 2020

Cited by 4 | Viewed by 3380

Abstract

Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of [...] Read more.

Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e., KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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15 pages, 1678 KiB

Open AccessArticle

In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

by Shana V. Stoddard, Kyra Dodson, Kamesha Adams and Davita L. Watkins

Int. J. Mol. Sci. 2020, 21(1), 219; https://doi.org/10.3390/ijms21010219 - 28 Dec 2019

Cited by 6 | Viewed by 2950

Abstract

Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development [...] Read more.

Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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12 pages, 3477 KiB

Open AccessArticle

HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina

by Mi Sun Sung, Hwan Heo, Gwang Hyeon Eom, So Young Kim, Helong Piao, Yue Guo and Sang Woo Park

Int. J. Mol. Sci. 2019, 20(20), 5159; https://doi.org/10.3390/ijms20205159 - 17 Oct 2019

Cited by 16 | Viewed by 2901

Abstract

The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL/6J mice were subjected to constant elevation of [...] Read more.

The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL/6J mice were subjected to constant elevation of intraocular pressure for 60 min to induce retinal IR injury. Expression of macroglial and microglial cell markers (GFAP and Iba1), hypoxia inducing factor (HIF)-1α, and histone acetylation was analyzed after IR injury. To investigate the role of HDACs in the activation of glial cells, overexpression of HDAC1 and HDAC2 isoforms was performed. To determine the effect of HDAC inhibition on RGC survival, trichostatin-A (TSA, 2.5 mg/kg) was injected intraperitoneally. After IR injury, retinal GFAP, Iba1, and HIF-1α were upregulated. Conversely, retinal histone acetylation was downregulated. Notably, adenoviral-induced overexpression of HDAC2 enhanced glial activation following IR injury, whereas overexpression of HDAC1 did not significantly affect glial activation. TSA treatment significantly increased RGC survival after IR injury. Our results suggest that increased activity of HDAC2 is closely related to glial activation in a mouse model of retinal IR injury and inhibition of HDACs by TSA showed neuroprotective potential in retinas with IR injuries. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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Review

Jump to: Research

20 pages, 1135 KiB

Open AccessReview

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

by Sena Kim, Srikanth Santhanam, Sora Lim and Jaebok Choi

Int. J. Mol. Sci. 2020, 21(12), 4281; https://doi.org/10.3390/ijms21124281 - 16 Jun 2020

Cited by 9 | Viewed by 4136

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft [...] Read more.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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18 pages, 710 KiB

Open AccessReview

The Role of Histone Acetylation and the Microbiome in Phytochemical Efficacy for Cardiovascular Diseases

by Levi W. Evans, Maheshi Athukorala, Kristina Martinez-Guryn and Bradley S. Ferguson

Int. J. Mol. Sci. 2020, 21(11), 4006; https://doi.org/10.3390/ijms21114006 - 03 Jun 2020

Cited by 10 | Viewed by 3578

Abstract

Cardiovascular diseases (CVD) are the main cause of death worldwide and create a substantial financial burden. Emerging studies have begun to focus on epigenetic targets and re-establishing healthy gut microbes as therapeutic options for the treatment and prevention of CVD. Phytochemicals, commonly found [...] Read more.

Cardiovascular diseases (CVD) are the main cause of death worldwide and create a substantial financial burden. Emerging studies have begun to focus on epigenetic targets and re-establishing healthy gut microbes as therapeutic options for the treatment and prevention of CVD. Phytochemicals, commonly found in fruits and vegetables, have been shown to exert a protective effect against CVD, though their mechanisms of action remain incompletely understood. Of interest, phytochemicals such as curcumin, resveratrol and epigallocatechin gallate (EGCG) have been shown to regulate both histone acetylation and microbiome re-composition. The purpose of this review is to highlight the microbiome–epigenome axis as a therapeutic target for food bioactives in the prevention and/or treatment of CVD. Specifically, we will discuss studies that highlight how the three phytochemicals above alter histone acetylation leading to global changes in gene expression and CVD protection. Then, we will expand upon these phytochemicals to discuss the impact of phytochemical–microbiome–histone acetylation interaction in CVD. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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21 pages, 1199 KiB

Open AccessReview

Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells

by Andreas von Knethen, Ulrike Heinicke, Andreas Weigert, Kai Zacharowski and Bernhard Brüne

Int. J. Mol. Sci. 2020, 21(7), 2356; https://doi.org/10.3390/ijms21072356 - 29 Mar 2020

Cited by 32 | Viewed by 5691

Abstract

Regulatory T cells (T_regs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4⁺Forkhead box protein3⁺ (CD4⁺FOXP3⁺), these cells are a subset of CD4⁺ T lymphocytes and can originate from [...] Read more.

Regulatory T cells (T_regs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4⁺Forkhead box protein3⁺ (CD4⁺FOXP3⁺), these cells are a subset of CD4⁺ T lymphocytes and can originate from the thymus (tT_regs) or from the periphery (pT_regs). The malfunction of CD4⁺ T_regs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional T_regs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking T_reg differentiation might be favorable in sepsis patients. It has been shown that T_regs can be generated from conventional naïve T cells, called iT_regs, due to their induced differentiation. Moreover, T_regs can be effectively expanded in vitro based on blood-derived tT_regs. Taking into consideration that the suppressive role of T_regs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of T_regs in this review in detail. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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18 pages, 2479 KiB

Open AccessReview

FcεRI-HDAC3-MCP1 Signaling Axis Promotes Passive Anaphylaxis Mediated by Cellular Interactions

by Misun Kim, Yoojung Kwon, Hyun Suk Jung, Youngmi Kim and Dooil Jeoung

Int. J. Mol. Sci. 2019, 20(19), 4964; https://doi.org/10.3390/ijms20194964 - 08 Oct 2019

Cited by 10 | Viewed by 5214

Abstract

Anaphylaxis is an acute and life-threatening systemic reaction. Food, drug, aero-allergen and insect sting are known to induce anaphylaxis. Mast cells and basophils are known to mediate Immunoglobulin E (IgE)-dependent anaphylaxis, while macrophages, neutrophils and basophils mediate non IgE-dependent anaphylaxis. Histone deacetylases (HDACs) [...] Read more.

Anaphylaxis is an acute and life-threatening systemic reaction. Food, drug, aero-allergen and insect sting are known to induce anaphylaxis. Mast cells and basophils are known to mediate Immunoglobulin E (IgE)-dependent anaphylaxis, while macrophages, neutrophils and basophils mediate non IgE-dependent anaphylaxis. Histone deacetylases (HDACs) play various roles in biological processes by deacetylating histones and non-histones proteins. HDAC inhibitors can increase the acetylation of target proteins and affect various inflammatory diseases such as cancers and allergic diseases. HDAC3, a class I HDAC, is known to act as epigenetic and transcriptional regulators. It has been shown that HDAC3 can interact with the high-affinity Immunoglobulin E receptor (FcεRI), to mediate passive anaphylaxis and cellular interactions during passive anaphylaxis. Effects of HDAC3 on anaphylaxis, cellular interactions involving mast cells and macrophages during anaphylaxis, and any tumorigenic potential of cancer cells enhanced by mast cells will be discussed in this review. Roles of microRNAs that form negative feedback loops with hallmarks of anaphylaxis such as HDAC3 in anaphylaxis and cellular interactions will also be discussed. The roles of MCP1 regulated by HDAC3 in cellular interactions during anaphylaxis are discussed. Roles of exosomes in cellular interactions mediated by HDAC3 during anaphylaxis are also discussed. Thus, review might provide clues for development of drugs targeting passive anaphylaxis. Full article

(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)

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