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1.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360712

RESUMO

Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Modelos Neurológicos , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Fatores de Transcrição/metabolismo , Acetilação , Animais , Humanos
2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445348

RESUMO

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.


Assuntos
Fibroblastos/fisiologia , Histonas/metabolismo , PPAR gama/fisiologia , Ligamento Periodontal/fisiologia , Acetilação , Diferenciação Celular/genética , Células Cultivadas , Cementogênese/genética , Cementogênese/fisiologia , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Histonas/química , Humanos , Osteogênese/genética , Osteogênese/fisiologia , Ligamento Periodontal/citologia , Processamento de Proteína Pós-Traducional/genética
3.
Elife ; 102021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431785

RESUMO

Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.


Assuntos
Carcinogênese/genética , Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Transformação Celular Neoplásica , Feminino , Células HEK293 , Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/metabolismo
4.
Arch Insect Biochem Physiol ; 108(2): e21838, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34350621

RESUMO

Silkworm is not only an ideal insect model with a biological significance, but it is also crucially important in sericulture and bioreactors. Bombyx mori nucleopolyhedrovirus (BmNPV) is a principal pathogen of silkworm. However, the molecular mechanism underlying BmNPV invasion is still unclear. Based on our previous acetylome research findings of B. mori after BmNPV infection, here, we focused on silkworm alteration/deficiency in activation-3 (BmAda3). The acetylation of K124 and K128 were significantly reduced (0.66-fold) upon the virus challenge. Due to the interaction between Ada3 and P53, acetylation-mimic K124Q/K128Q and deacetylation-mimic K124R/K128R mutants of BmAda3 were constructed to explore the roles exerted by the acetylation modification of BmAda3 on P53. Yeast two-hybrid and IP results revealed that both BmAda3 and its deacetylation mutants (K124R/K128R) interacted with P53. Interestingly, we found that the deacetylation mutants (K124R/K128R) of BmAda3 significantly promoted the stability of P53. Since P53 is a proapoptotic factor, cell apoptosis was detected. We established that the deacetylation of BmAda3 at K124/K128 facilitated cellular apoptosis during BmNPV infection. Finally, viral proliferation was analyzed, and the results indicated that virus generation was reduced by K124/K128 deacetylation. Our report, based on the deacetylation of two lysine sites 124/128 of BmAda3, shows possible regulatory pathways of BmNPV proliferation and provides novel insights into the development of antiviral agents.


Assuntos
Apoptose , Bombyx/virologia , Histona Acetiltransferases , Nucleopoliedrovírus/patogenicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Bombyx/genética , Bombyx/metabolismo , Genes de Insetos , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Mutação
5.
Nat Commun ; 12(1): 4618, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326347

RESUMO

The transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the histone acetyltransferase (HAT) domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.


Assuntos
Núcleo Celular/metabolismo , Cromatina/metabolismo , Proteína p300 Associada a E1A/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Células Cultivadas , Proteína p300 Associada a E1A/química , Humanos , Domínios Proteicos
6.
Nat Commun ; 12(1): 4404, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285225

RESUMO

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-ß (TGFß) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFß induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFß on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFß-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFß signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.


Assuntos
Autofagia/genética , Epigênese Genética , Histona Acetiltransferases/metabolismo , Escleroderma Sistêmico/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Biópsia , Estudos de Casos e Controles , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Fibroblastos , Fibrose , Técnicas de Inativação de Genes , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Células NIH 3T3 , Cultura Primária de Células , Receptores de Fatores de Crescimento Transformadores beta , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Proteína Smad3/metabolismo , Adulto Jovem
7.
Chem Commun (Camb) ; 57(55): 6788-6791, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34137401

RESUMO

Histone lysine methylation and acetylation are important posttranslational modifications that regulate gene expression in humans. Due to the interplay of these two modifications, new chemical methods to study lysine posttranslational modifications are highly desired. Here, we report the use of γ-difluorolysine as a lysine mimic and 19F NMR probe for examinations of histone methylation and acetylation.


Assuntos
Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Lisina/química , Espectroscopia de Ressonância Magnética/métodos , Acetilação , Metilação
8.
Immunity ; 54(8): 1683-1697.e3, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34107298

RESUMO

Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/imunologia , Células Enteroendócrinas/metabolismo , Microbioma Gastrointestinal/imunologia , Histona Acetiltransferases/metabolismo , Intestinos/imunologia , Acetatos/imunologia , Acetilcoenzima A/metabolismo , Animais , Montagem e Desmontagem da Cromatina/fisiologia , Drosophila melanogaster/microbiologia , Ecdisona/metabolismo , Imunidade Inata/imunologia , Intestinos/microbiologia , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Interferência de RNA , Transdução de Sinais/imunologia , Taquicininas/metabolismo
9.
Eur J Med Chem ; 223: 113649, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34186233

RESUMO

O-GlcNAcylation is a dynamic post-translational modification mediated by O-linked ß-N-acetylglucosamine transferase (OGT) and O-GlcNAc hydrolase (OGA), that adds or removes a single ß-N-acetylglucosamine (GlcNAc) moiety to or from serine/threonine residues of nucleocytosolic and mitochondrial proteins, respectively. The perturbed homeostasis of O-GlcNAc cycling results in several pathological conditions. Human OGA is a promising therapeutic target in diseases where aberrantly low levels of O-GlcNAc are experienced, such as tauopathy in Alzheimer's disease. A new class of potent OGA inhibitors, 2-acetamido-2-deoxy-d-glucono-1,5-lactone (thio)semicarbazones, have been identified. Eight inhibitors were designed and synthesized in five steps starting from d-glucosamine and with 15-55% overall yields. A heterologous OGA expression protocol with strain selection and isolation has been optimized that resulted in stable, active and full length human OGA (hOGA) isomorph. Thermal denaturation kinetics of hOGA revealed environmental factors affecting hOGA stability. From kinetics experiments, the synthesized compounds proved to be efficient competitive inhibitors of hOGA with Ki-s in the range of ∼30-250 nM and moderate selectivity with respect to lysosomal ß-hexosaminidases. In silico studies consisting of Prime protein-ligand refinements, QM/MM optimizations and QM/MM-PBSA binding free energy calculations revealed the factors governing the observed potencies, and led to design of the most potent analogue 2-acetamido-2-deoxy-d-glucono-1,5-lactone 4-(2-naphthyl)-semicarbazone 6g (Ki = 36 nM). The protocol employed has applications in future structure based inhibitor design targeting OGA.


Assuntos
Antígenos de Neoplasias/metabolismo , Inibidores Enzimáticos/química , Histona Acetiltransferases/metabolismo , Hialuronoglucosaminidase/metabolismo , Lactonas/química , Semicarbazonas/química , Antígenos de Neoplasias/genética , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/genética , Humanos , Hialuronoglucosaminidase/antagonistas & inibidores , Hialuronoglucosaminidase/genética , Cinética , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Estabilidade Proteica , Teoria Quântica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Semicarbazonas/metabolismo , Relação Estrutura-Atividade
10.
Cell Death Dis ; 12(7): 622, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135314

RESUMO

Accumulated evidence shows that OGT-mediated O-GlcNAcylation plays an important role in response to DNA damage repair. However, it is unclear if the "eraser" O-GlcNAcase (OGA) participates in this cellular process. Here, we examined the molecular mechanisms and biological functions of OGA in DNA damage repair, and found that OGA was recruited to the sites of DNA damage and mediated deglycosylation following DNA damage. The recruitment of OGA to DNA lesions is mediated by O-GlcNAcylation events. Moreover, we have dissected OGA using deletion mutants and found that C-terminal truncated OGA including the pseudo HAT domain was required for the recruitment of OGA to DNA lesions. Using unbiased protein affinity purification, we found that the pseudo HAT domain was associated with DNA repair factors including NONO and the Ku70/80 complex. Following DNA damage, both NONO and the Ku70/80 complex were O-GlcNAcylated by OGT. The pseudo HAT domain was required to recognize NONO and the Ku70/80 complex for their deglycosylation. Suppression of the deglycosylation prolonged the retention of NONO at DNA lesions and delayed NONO degradation on the chromatin, which impaired non-homologus end joining (NHEJ). Collectively, our study reveals that OGA-mediated deglycosylation plays a key role in DNA damage repair.


Assuntos
Antígenos de Neoplasias/metabolismo , Núcleo Celular/enzimologia , Dano ao DNA , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Histona Acetiltransferases/metabolismo , Hialuronoglucosaminidase/metabolismo , Autoantígeno Ku/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/metabolismo , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/efeitos da radiação , Proliferação de Células , Proteínas de Ligação a DNA/genética , Glicosilação , Células HEK293 , Histona Acetiltransferases/genética , Humanos , Hialuronoglucosaminidase/genética , Autoantígeno Ku/genética , Domínios Proteicos , Proteínas de Ligação a RNA/genética , Especificidade por Substrato
11.
Nat Commun ; 12(1): 3253, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059674

RESUMO

Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.


Assuntos
Autorrenovação Celular/genética , Músculo Esquelético/lesões , Fator de Transcrição PAX7/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/fisiologia , Acetilação , Animais , Células COS , Sistemas CRISPR-Cas , Cardiotoxinas/administração & dosagem , Cardiotoxinas/toxicidade , Diferenciação Celular/genética , Chlorocebus aethiops , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Mutagênese , Cultura Primária de Células , Regiões Promotoras Genéticas , Células Sf9 , Sirtuína 2/genética , Sirtuína 2/metabolismo , Spodoptera , Ativação Transcricional
12.
Adv Protein Chem Struct Biol ; 125: 149-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33931138

RESUMO

The development of cancer is a complex phenomenon driven by various extrinsic as well as intrinsic risk factors including epigenetic modifications. These post-translational modifications are encountered in diverse cancer cells and appear for a relatively short span of time. These changes can significantly affect various oncogenic genes and proteins involved in cancer initiation and progression. Histone lysine acetylation and deacetylation processes are controlled by two opposing classes of enzymes that modulate gene regulation either by adding an acetyl moiety on a histone lysine residue by histone lysine acetyltransferases (KATs) or via removing it by histone deacetylases (KDACs). Deregulated KAT activity has been implicated in the development of several diseases including cancer and can be targeted for the development of anti-neoplastic drugs. Here, we describe the predominant epigenetic changes that can affect key KAT superfamily members during carcinogenesis and briefly highlight the pharmacological potential of employing lysine acetyltransferase inhibitors (KATi) for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Histona Acetiltransferases , Proteínas de Neoplasias , Neoplasias , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia
13.
J Chem Theory Comput ; 17(6): 3783-3796, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34032440

RESUMO

Biomolecules with metal ion(s) (e.g., metalloproteins) play many important biological roles. However, accurate structural determination of metalloproteins, particularly those containing transition metal ion(s), is challenging due to their complicated electronic structure, complex bonding of metal ions, and high number of conformations in biomolecules. Quantum refinement, which was proposed to combine crystallographic data with computational chemistry methods by several groups, can improve the local structures of some proteins. In this study, a quantum refinement method combining several multiscale computational schemes with experimental (X-ray diffraction) information was developed for metalloproteins. Various quantum refinement approaches using different ONIOM (our own N-layered integrated molecular orbital and molecular mechanics) combinations of quantum mechanics (QM), semiempirical (SE), and molecular mechanics (MM) methods were conducted to assess the performance and reliability on the refined local structure in two metalloproteins. The structures for two (Cu- or Zn-containing) metalloproteins were refined by combining two-layer ONIOM2(QM1/QM2) and ONIOM2(QM/MM) and three-layer ONIOM3(QM1/QM2/MM) schemes with experimental data. The accuracy of the quantum-refined metal binding sites was also examined and compared in these multiscale quantum refinement calculations. ONIOM3(QM/SE/MM) schemes were found to give good results with lower computational costs and were proposed to be a good choice for the multiscale computational scheme for quantum refinement calculations of metal binding site(s) in metalloproteins with high efficiency. Additionally, a two-center ONIOM approach was employed to speed up the quantum refinement calculations for the Zn metalloprotein with two remote active sites/ligands. Moreover, a recent quantum-embedding wavefunction-in-density functional theory (WF-in-DFT) method was also adopted as the high-level method in unprecedented ONIOM2(CCSD-in-B3LYP/MM) and ONIOM3(CCSD-in-B3LYP/SE/MM) calculations, which can be regarded as novel pseudo-three- and pseudo-four-layer ONIOM methods, respectively, to refine the key Zn binding site at the coupled-cluster singles and doubles (CCSD) level. These refined results indicate that multiscale quantum refinement schemes can be used to improve the structural accuracy obtained for local metal binding site(s) in metalloproteins with high efficiency.


Assuntos
Metaloproteínas/química , Teoria Quântica , Azurina/química , Azurina/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Ligantes , Metaloproteínas/metabolismo , Metais/química , Simulação de Dinâmica Molecular
14.
Cell Death Dis ; 12(6): 549, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039960

RESUMO

Hepatocellular carcinoma (HCC) is a common primary liver malignancy lacking effective molecularly-targeted therapies. HBO1 (lysine acetyltransferase 7/KAT7) is a member of MYST histone acetyltransferase family. Its expression and potential function in HCC are studied. We show that HBO1 mRNA and protein expression is elevated in human HCC tissues and HCC cells. HBO1 expression is however low in cancer-surrounding normal liver tissues and hepatocytes. In HepG2 and primary human HCC cells, shRNA-induced HBO1 silencing or CRISPR/Cas9-induced HBO1 knockout potently inhibited cell viability, proliferation, migration, and invasion, while provoking mitochondrial depolarization and apoptosis induction. Conversely, ectopic overexpression of HBO1 by a lentiviral construct augmented HCC cell proliferation, migration and invasion. In vivo, xenografts-bearing HBO1-KO HCC cells grew significantly slower than xenografts with control HCC cells in severe combined immunodeficient mice. These results suggest HBO1 overexpression is important for HCC cell progression.


Assuntos
Carcinoma Hepatocelular/genética , Histona Acetiltransferases/metabolismo , Neoplasias Hepáticas/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID
15.
Plant Cell ; 33(4): 961-979, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-33793815

RESUMO

Epigenetic mechanisms play diverse roles in the regulation of genome stability in eukaryotes. In Arabidopsis thaliana, genome stability is maintained during DNA replication by the H3.1K27 methyltransferases ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) and ATXR6, which catalyze the deposition of K27me1 on replication-dependent H3.1 variants. The loss of H3.1K27me1 in atxr5 atxr6 double mutants leads to heterochromatin defects, including transcriptional de-repression and genomic instability, but the molecular mechanisms involved remain largely unknown. In this study, we identified the transcriptional co-activator and conserved histone acetyltransferase GCN5 as a mediator of transcriptional de-repression and genomic instability in the absence of H3.1K27me1. GCN5 is part of a SAGA-like complex in plants that requires the GCN5-interacting protein ADA2b and the chromatin remodeler CHR6 to mediate the heterochromatic defects in atxr5 atxr6 mutants. Our results also indicate that Arabidopsis GCN5 acetylates multiple lysine residues on H3.1 variants, but H3.1K27 and H3.1K36 play essential functions in inducing genomic instability in the absence of H3.1K27me1. Finally, we show that H3.1K36 acetylation by GCN5 is negatively regulated by H3.1K27me1 in vitro. Overall, this work reveals a key molecular role for H3.1K27me1 in maintaining transcriptional silencing and genome stability in heterochromatin by restricting GCN5-mediated histone acetylation in plants.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Instabilidade Genômica , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Acetilação , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Inativação Gênica , Genoma de Planta , Heterocromatina/genética , Heterocromatina/metabolismo , Histona Acetiltransferases/genética , Histonas/genética , Lisina/genética , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Mutação , Plantas Geneticamente Modificadas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Life Sci ; 277: 119504, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872660

RESUMO

The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Among these, histone deacetylases (HDAC) deacetylate the histone and induce gene repression thereby leading to cancer. In contrast, histone acetyl transferases (HATs) that include GCN5, p300/CBP, PCAF, Tip 60 acetylate the histones. HDAC inhibitors are potent drug molecules that can induce acetylation of histones at lysine residues and induce open chromatin conformation at tumor suppressor gene loci and thus resulting in tumor suppression. The key processes regulated by HDAC inhibitors include cell-cycle arrest, chemo-sensitization, apoptosis induction, upregulation of tumor suppressors. Even though FDA approved drugs are confined mainly to haematological malignancies, the research on HDAC inhibitors in glioblastoma multiforme and triple negative breast cancer (TNBC) are providing positive results. Thus, several combinations of HDAC inhibitors along with DNA methyl transferase inhibitors and histone methyl transferase inhibitors are in clinical trials. This review focuses on how HDAC inhibitors regulate the expression of coding and non-coding genes with specific emphasis on their anti-cancer potential.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Acetilação , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cromatina/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Epigenômica/métodos , Expressão Gênica/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
17.
Biochem Biophys Res Commun ; 557: 273-279, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33894414

RESUMO

Recently, the novel coronavirus (SARS-CoV-2), which has spread from China to the world, was declared a global public health emergency, which causes lethal respiratory infections. Acetylation of several proteins plays essential roles in various biological processes, such as viral infections. We reported that the nucleoproteins of influenza virus and Zaire Ebolavirus were acetylated, suggesting that these modifications contributed to the molecular events involved in viral replication. Similar to influenza virus and Ebolavirus, the coronavirus also contains single-stranded RNA, as its viral genome interacts with the nucleocapsid (N) proteins. In this study, we report that SARS-CoV and SARS-CoV-2 N proteins are strongly acetylated by human histone acetyltransferases, P300/CBP-associated factor (PCAF), and general control nonderepressible 5 (GCN5), but not by CREB-binding protein (CBP) in vitro. Liquid chromatography-mass spectrometry analyses identified 2 and 12 acetyl-lysine residues from SARS-CoV and SARS-CoV-2 N proteins, respectively. Particularly in the SARS-CoV-2 N proteins, the acetyl-lysine residues were localized in or close to several functional sites, such as the RNA interaction domains and the M-protein interacting site. These results suggest that acetylation of SARS-CoV-2 N proteins plays crucial roles in their functions.


Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Histona Acetiltransferases/metabolismo , Vírus da SARS/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Proteína de Ligação a CREB/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/química , Humanos , Modelos Moleculares , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Vírus da SARS/química , SARS-CoV-2/química
18.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926075

RESUMO

Chromatin organization is developmentally regulated by epigenetic changes mediated by histone-modifying enzymes and chromatin remodeling complexes. In Drosophila melanogaster, the Tip60 chromatin remodeling complex (dTip60) play roles in chromatin regulation, which are shared by evolutionarily-related complexes identified in animal and plants. Recently, it was found that most subunits previously assigned to the dTip60 complex are shared by two related complexes, DOM-A.C and DOM-B.C, defined by DOM-A and DOM-B isoforms, respectively. In this work, we combined classical genetics, cell biology, and reverse genetics approaches to further investigate the biological roles played during Drosophila melanogaster development by a number of subunits originally assigned to the dTip60 complex.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/genética , Proteínas de Drosophila/genética , Histona Acetiltransferases/genética , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Epigênese Genética/genética , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Cromossomos Politênicos/genética , Cromossomos Politênicos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807238

RESUMO

The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein-Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Remarkably, we observed that the commensal gut microbiota composition in a cohort of RSTS patients is significantly depleted in butyrate-producing bacteria compared to healthy siblings. We demonstrate that the effects of butyrate and the differences in microbiota composition are conserved in a Drosophila melanogaster mutant for CBP, enabling future dissection of the gut-host interactions in an in vivo RSTS model. This study sheds light on microbiota composition in a chromatinopathy, paving the way for novel therapeutic interventions.


Assuntos
Butiratos/metabolismo , Síndrome de Rubinstein-Taybi/metabolismo , Síndrome de Rubinstein-Taybi/microbiologia , Acetilação , Adolescente , Animais , Butiratos/farmacologia , Proteína de Ligação a CREB/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Modelos Animais de Doenças , Drosophila melanogaster/metabolismo , Proteína p300 Associada a E1A/metabolismo , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/fisiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Mutação , Processamento de Proteína Pós-Traducional , Fatores de Transcrição de p300-CBP/metabolismo
20.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799504

RESUMO

Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histona Acetiltransferases/genética , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Terpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Garcinia/química , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Extratos Vegetais/química
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