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Frontiers in Immunology 2022The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD-dependent deacetylase belonging to the sirtuin family, is a post-translational... (Review)
Review
The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD-dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional and post-transcriptional levels. We also summarize factors that influence SIRT1 activity including the NAD/NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases.
Topics: Histones; Humans; Inflammation; NAD; Sirtuin 1; Sirtuins
PubMed: 35359990
DOI: 10.3389/fimmu.2022.831168 -
Cold Spring Harbor Perspectives in... Apr 2014Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In... (Review)
Review
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.
Topics: Arginase; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Models, Biological; Protein Processing, Post-Translational; Protein Structure, Tertiary; Saccharomyces cerevisiae; Sirtuins; Substrate Specificity
PubMed: 24691964
DOI: 10.1101/cshperspect.a018713 -
Cardiovascular Research Jun 2022The histone deacetylases (HDACs) are a family of enzymes that catalyse lysine deacetylation of both histone and non-histone proteins. Here, we review, summarize, and... (Review)
Review
The histone deacetylases (HDACs) are a family of enzymes that catalyse lysine deacetylation of both histone and non-histone proteins. Here, we review, summarize, and provide perspectives on the literature regarding one such HDAC, HDAC1, in endothelial biology. In the endothelium, HDAC1 mediates the effects of external and environmental stimuli by regulating major endothelial functions such as angiogenesis, inflammatory signalling, redox homeostasis, and nitric oxide signalling. Angiogenesis is most often, but not exclusively, repressed by endothelial HDAC1. The regulation of inflammatory signalling is more complex as HDAC1 promotes or suppresses inflammatory signalling depending upon the environmental stimuli. HDAC1 is protective in models of atherosclerosis where loss of HDAC1 results in increased cytokine and cell adhesion molecule (CAM) abundance. In other models, HDAC1 promotes inflammation by increasing CAMs and repressing claudin-5 expression. Consistently, from many investigations, HDAC1 decreases antioxidant enzyme expression and nitric oxide production in the endothelium. HDAC1 decreases antioxidant enzyme expression through the deacetylation of histones and transcription factors, and also regulates nitric oxide production through regulating both the expression and activity of nitric oxide synthase 3. The HDAC1-dependent regulation of endothelial function through the deacetylation of both histone and non-histone proteins ultimately impacts whole animal physiology and health.
Topics: Animals; Antioxidants; Endothelium; Histone Deacetylase 1; Histone Deacetylases; Histones; Nitric Oxide
PubMed: 34264338
DOI: 10.1093/cvr/cvab198 -
International Journal of Molecular... Oct 2021Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time... (Review)
Review
Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Epigenesis, Genetic; Histone Code; Histones; Humans; Molecular Targeted Therapy
PubMed: 34769131
DOI: 10.3390/ijms222111701 -
Nature Sep 2022Dividing eukaryotic cells package extremely long chromosomal DNA molecules into discrete bodies to enable microtubule-mediated transport of one genome copy to each of...
Dividing eukaryotic cells package extremely long chromosomal DNA molecules into discrete bodies to enable microtubule-mediated transport of one genome copy to each of the newly forming daughter cells. Assembly of mitotic chromosomes involves DNA looping by condensin and chromatin compaction by global histone deacetylation. Although condensin confers mechanical resistance to spindle pulling forces, it is not known how histone deacetylation affects material properties and, as a consequence, segregation mechanics of mitotic chromosomes. Here we show how global histone deacetylation at the onset of mitosis induces a chromatin-intrinsic phase transition that endows chromosomes with the physical characteristics necessary for their precise movement during cell division. Deacetylation-mediated compaction of chromatin forms a structure dense in negative charge and allows mitotic chromosomes to resist perforation by microtubules as they are pushed to the metaphase plate. By contrast, hyperacetylated mitotic chromosomes lack a defined surface boundary, are frequently perforated by microtubules and are prone to missegregation. Our study highlights the different contributions of DNA loop formation and chromatin phase separation to genome segregation in dividing cells.
Topics: Acetylation; Chromatin; Chromosome Segregation; DNA; Histones; Microtubules; Mitosis; Phase Transition; Spindle Apparatus
PubMed: 35922507
DOI: 10.1038/s41586-022-05027-y -
Journal of the American Chemical Society Mar 2023The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and...
The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.
Topics: Nucleosomes; Histones; Chromatin; Sirtuins; Acetylation; Glycosyltransferases; Catalysis
PubMed: 36930461
DOI: 10.1021/jacs.2c13512 -
Nature Aug 2023Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation. The Rpd3 small (Rpd3S) complex recognizes histone H3...
Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation. The Rpd3 small (Rpd3S) complex recognizes histone H3 trimethylation on lysine 36 (H3K36me3) and deacetylates histones H3 and H4 at multiple sites across transcribed regions. Here we solved the cryo-electron microscopy structures of Saccharomyces cerevisiae Rpd3S in its free and H3K36me3 nucleosome-bound states. We demonstrated a unique architecture of Rpd3S, in which two copies of Eaf3-Rco1 heterodimers are asymmetrically assembled with Rpd3 and Sin3 to form a catalytic core complex. Multivalent recognition of two H3K36me3 marks, nucleosomal DNA and linker DNAs by Eaf3, Sin3 and Rco1 positions the catalytic centre of Rpd3 next to the histone H4 N-terminal tail for deacetylation. In an alternative catalytic mode, combinatorial readout of unmethylated histone H3 lysine 4 and H3K36me3 by Rco1 and Eaf3 directs histone H3-specific deacetylation except for the registered histone H3 acetylated lysine 9. Collectively, our work illustrates dynamic and diverse modes of multivalent nucleosomal engagement and methylation-guided deacetylation by Rpd3S, highlighting the exquisite complexity of epigenetic regulation with delicately designed multi-subunit enzymatic machineries in transcription and beyond.
Topics: Acetylation; Cryoelectron Microscopy; DNA, Fungal; Epigenesis, Genetic; Histones; Lysine; Nucleosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Methylation; Multiprotein Complexes
PubMed: 37468628
DOI: 10.1038/s41586-023-06349-1 -
Cancer Communications (London, England) Nov 2023Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m A) is the most prevalent...
BACKGROUND
Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m A modifications in the regulation of tumorigenesis of ocular melanoma.
METHODS
Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m A levels of FAT4 were affected.
RESULTS
First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m A modification in tumorigenesis.
CONCLUSIONS
These results demonstrate that HDACis exert anti-cancer effects by orchestrating m A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.
Topics: Humans; Methylation; Histones; Histone Deacetylases; Cell Line, Tumor; Melanoma; Carcinogenesis; RNA; RNA-Binding Proteins; Methyltransferases
PubMed: 37466203
DOI: 10.1002/cac2.12471 -
Nature Oct 2023Lysine residues in histones and other proteins can be modified by post-translational modifications that encode regulatory information. Lysine acetylation and methylation...
Lysine residues in histones and other proteins can be modified by post-translational modifications that encode regulatory information. Lysine acetylation and methylation are especially important for regulating chromatin and gene expression. Pathways involving these post-translational modifications are targets for clinically approved therapeutics to treat human diseases. Lysine methylation and acetylation are generally assumed to be mutually exclusive at the same residue. Here we report cellular lysine residues that are both methylated and acetylated on the same side chain to form N-acetyl-N-methyllysine (Kacme). We show that Kacme is found on histone H4 (H4Kacme) across a range of species and across mammalian tissues. Kacme is associated with marks of active chromatin, increased transcriptional initiation and is regulated in response to biological signals. H4Kacme can be installed by enzymatic acetylation of monomethyllysine peptides and is resistant to deacetylation by some HDACs in vitro. Kacme can be bound by chromatin proteins that recognize modified lysine residues, as we demonstrate with the crystal structure of acetyllysine-binding protein BRD2 bound to a histone H4Kacme peptide. These results establish Kacme as a cellular post-translational modification with the potential to encode information distinct from methylation and acetylation alone and demonstrate that Kacme has all the hallmarks of a post-translational modification with fundamental importance to chromatin biology.
Topics: Animals; Humans; Acetylation; Chromatin; Histones; Lysine; Methylation; Peptides; Protein Processing, Post-Translational; Transcription Initiation Site; Histone Deacetylases
PubMed: 37731000
DOI: 10.1038/s41586-023-06565-9 -
Oxidative Medicine and Cellular... 2022Aging is an inevitable consequence of life, and during this process, the epigenetic landscape changes and reactive oxygen species (ROS) accumulation increases.... (Review)
Review
Aging is an inevitable consequence of life, and during this process, the epigenetic landscape changes and reactive oxygen species (ROS) accumulation increases. Inevitably, these changes are common in many age-related diseases, including neurodegeneration, hypertension, and cardiovascular diseases. In the current research, histone deacetylation 4 (HDAC4) was studied as a potential therapeutic target in vascular senescence. HDAC4 is a specific class II histone deacetylation protein that participates in epigenetic modifications and deacetylation of heat shock proteins and various transcription factors. There is increasing evidence to support that HDAC4 is a potential therapeutic target, and developments in the synthesis and testing of HDAC4 inhibitors are now gaining interest from academia and the pharmaceutical industry.
Topics: Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hypertension; Protein Processing, Post-Translational; Repressor Proteins
PubMed: 35814270
DOI: 10.1155/2022/3087916