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1.
Methods Mol Biol ; 2519: 155-161, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36066720

RESUMO

Posttranslational modifications (PTMs) of histones, such as lysine acetylation and ubiquitination, regulate chromatin structure and gene expression. In living organisms, histone PTMs are catalyzed by histone-modifying enzymes. Here, we describe an entirely chemical method to introduce histone modifications in living cells without genetic manipulation. The chemical catalyst PEG-LANA-DSSMe activates a thioester acetyl donor, N,S-diacetylcysteamine (NAC-Ac), and promotes regioselective, synthetic histone acetylation at H2BK120 in living cells.


Assuntos
Histonas , Processamento de Proteína Pós-Traducional , Acetilação , Catálise , Histonas/metabolismo , Lisina/metabolismo
2.
Methods Mol Biol ; 2519: 163-185, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36066721

RESUMO

Posttranslational modifications of histone are intimately related to chromatin/chromosome-mediated cellular events. Among all, the roles of histone modifications including acetylation, methylation, ubiquitination, and SUMOylation of lysine or arginine residue of nucleosome core histones in gene expression have been intensively studied. Genome-wide profiles of histone modification marks revealed their combinatorial organization in the functional features of chromatin. Analysis of histone modification by chromatin immunoprecipitation (ChIP) is one of the standard assays to examine chromatin states. Although high-throughput sequencing analysis (ChIP-seq) is now widely conducted, classical ChIP-qPCR analysis has advantages in investigation of multiple histone modification marks at a target site simply through the use of relatively small numbers of cells. Since ChIP-qPCR is devoid of biases caused by overamplification and inaccurate mapping of sequencing reads, it is a more reliable quantification method than genome-wide ChIP-seq especially for analyses of the low-mappability regions, which harbor many repetitive sequences and/or highly homologous segmental multiplications as found in gene clusters. We have recently analyzed histone H3 and H4 modifications of the Zscan4 family gene loci in an 880 kb gene cluster and found that the atypical enhancer-like structure is formed upon derepression of Zscan4. In this chapter, we describe the detailed protocols for histone modification ChIP-assay of repeat-enriched gene cluster regions. The protocol here we applied to mouse ES cells, but the protocol is perfectly applicable to human cultured cells and specimens.


Assuntos
Código das Histonas , Histonas , Animais , Cromatina/genética , Imunoprecipitação da Cromatina/métodos , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Processamento de Proteína Pós-Traducional
3.
Epigenomics ; 14(5): 279-293, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35184601

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent form of cancer worldwide. Despite advancements made in treatment strategies, the fatality rate of HNSCC is very high. An accumulating body of evidence suggests that epigenetic modification of histones plays an influential role in the development and progression of the disease. In this review we discuss the role of epigenetic modifications in HNSCC and the inter-relationships of human papillomavirus oncoproteins and histone-modifying agents. Further, we explore the possibility of identifying these modifications as biomarkers for their use as drugs in treatment strategies.


Head and neck squamous cell carcinoma (HNSCC) is the most common kind of head and neck cancer. HNSCC can develop therapeutic resistance, making therapy more difficult. Many studies have found that epigenetic events play a key role in HNSCC. Better understanding epigenetic regulation could help discovery of biomarkers that help detect and diagnose HNSCC. This review will present recent studies, showing the importance of epigenetic regulation targeting histone modifications in the development of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Histonas , Epigênese Genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Código das Histonas , Histonas/metabolismo , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
4.
PLoS One ; 17(9): e0273518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36126055

RESUMO

The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.


Assuntos
Inibidores de Histona Desacetilases , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Vorinostat/farmacologia
5.
Genome Biol ; 23(1): 197, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127735

RESUMO

BACKGROUND: It is challenging to determine the effect of DNA methylation on the epigenetic landscape and the function in higher organisms due to the lack of DNA methylation-free mutants. RESULTS: Here, the analysis of a recently generated Arabidopsis mutant completely devoid of DNA methylation reveals that DNA methylation underpins the genome-wide landscape of histone modifications. Complete loss of DNA methylation causes an upheaval of the histone modification landscape, including complete loss of H3K9me2 and widespread redistribution of active and H3K27me3 histone marks, mostly owing to the role of DNA methylation in initiating H3K9me2 deposition and excluding active marks and repressive mark H3K27me3; CG and non-CG methylation can act independently at some genomic regions while they act cooperatively at many other regions. The transcriptional reprogramming upon loss of all DNA methylation correlates with the extensive redistribution or switches of the examined histone modifications. Histone modifications retained or gained in the DNA methylation-free mutant serve as DNA methylation-independent transcriptional regulatory signals: active marks promote genome transcription, whereas the repressive mark H3K27me3 compensates for the lack of DNA hypermethylation/H3K9me2 at multiple transposon families. CONCLUSIONS: Our results show that an intact DNA methylome constitutes the scaffolding of the epigenomic landscape in Arabidopsis and is critical for controlled genome transcription and ultimately for proper growth and development.


Assuntos
Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , DNA , Metilação de DNA , Epigênese Genética , Epigenômica , Histonas/metabolismo , Humanos
6.
Nat Commun ; 13(1): 5542, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130923

RESUMO

Polycomb (PcG) silencing is crucial for development, but how targets are specified remains incompletely understood. The cold-induced Polycomb Repressive Complex 2 (PRC2) silencing of Arabidopsis thaliana FLOWERING LOCUS C (FLC) provides an excellent system to elucidate PcG regulation. Association of the DNA binding protein VAL1 to FLC PcG nucleation regionis an important step. VAL1 co-immunoprecipitates APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and PRC1. Here, we show that ASAP and PRC1 are necessary for co-transcriptional repression and chromatin regulation at FLC. ASAP mutants affect FLC transcription in warm conditions, but the rate of FLC silencing in the cold is unaffected. PRC1-mediated H2Aub accumulation increases at the FLC nucleation region during cold, but unlike the PRC2-delivered H3K27me3, does not spread across the locus. H2Aub thus involved in the transition to epigenetic silencing at FLC, facilitating H3K27me3 accumulation and long-term epigenetic memory. Overall, our work highlights the importance of VAL1 as an assembly platform co-ordinating activities necessary for epigenetic silencing at FLC.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cromatina/genética , Cromatina/metabolismo , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Histonas/genética , Histonas/metabolismo , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb/metabolismo
7.
Sci Rep ; 12(1): 15735, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130958

RESUMO

Cocaine epigenetically regulates gene expression via changes in histone post-translational modifications (HPTMs). We previously found that the immediate early gene Nr4a1 is epigenetically activated by cocaine in mouse brain reward regions. However, few studies have examined multiple HPTMs at a single gene. Bivalent gene promoters are simultaneously enriched in both activating (H3K4me3 (K4)) and repressive (H3K27me3 (K27)) HPTMs. As such, bivalent genes are lowly expressed but poised for activity-dependent gene regulation. In this study, we identified K4&K27 bivalency at Nr4a1 following investigator-administered cocaine in male and female mice. We applied sequential chromatin immunoprecipitation and qPCR to define Nr4a1 bivalency and expression in striatum (STR), prefrontal cortex (PFC), and hippocampus (HPC). We used Pearson's correlation to quantify relationships within each brain region across treatment conditions for each sex. In female STR, cocaine increased Nr4a1 mRNA while maintaining Nr4a1 K4&K27 bivalency. In male STR, cocaine enriched repressive H3K27me3 and K4&K27 bivalency at Nr4a1 and maintained Nr4a1 mRNA. Furthermore, cocaine epigenetically regulated a putative NR4A1 target, Cartpt, in male PFC. This study defined the epigenetic regulation of Nr4a1 in reward brain regions in male and female mice following cocaine, and, thus, shed light on the biological relevance of sex to cocaine use disorder.


Assuntos
Cocaína , Histonas , Animais , Cromatina/genética , Cocaína/farmacologia , Epigênese Genética , Feminino , Histonas/genética , Histonas/metabolismo , Masculino , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , RNA Mensageiro/genética
8.
Front Endocrinol (Lausanne) ; 13: 932286, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133305

RESUMO

2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, including the kidney. The tumorigenesis resulting from overproduced 2HG has been attributed to the ability of 2HG alter gene expression by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation (TET) enzymes. Genes that regulate cellular differentiation are reportedly repressed, blocking differentiation of mesenchymal cells into myocytes, and adipocytes. In this report, the expression of the enzyme responsible for L2HG degradation, L-2HG dehydrogenase (L2HGDH), is knocked down, using lentiviral shRNA, as well as siRNA, in primary cultures of normal Renal Proximal Tubule (RPT) cells. The knockdown (KD) results in increased L-2HG levels, decreased demethylation of 5mC in genomic DNA, and increased methylation of H3 Histones. Consequences include reduced tubulogenesis by RPT cells in matrigel, and reduced expression of molecular markers of differentiation, including membrane transporters as well as HNF1α and HNF1ß, which regulate their transcription. These results are consistent with the hypothesis that oncometabolite 2HG blocks RPT differentiation by altering the methylation status of chromatin in a manner that impedes the transcriptional events required for normal differentiation. Presumably, similar alterations are responsible for promoting the expansion of renal cancer stem-cells, increasing their propensity for malignant transformation.


Assuntos
Dioxigenases , Histonas , Diferenciação Celular/genética , Cromatina , Dioxigenases/metabolismo , Epigênese Genética , Glutaratos , Histonas/metabolismo , Ácidos Cetoglutáricos/metabolismo , Rim/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Oxirredutases/metabolismo , RNA Interferente Pequeno
9.
Dis Markers ; 2022: 9883831, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133436

RESUMO

Liver fibrosis results from the formation of fibrous scars of hepatic stellate cells by various chronic liver diseases. Considering that the liver is the most important metabolic organ in the human body, exploring the metabolic characteristics of liver fibrosis is expected to discover new markers and therapeutic targets. In this study, we first used mouse model to verify that both lactate content and histone acetylation levels were significantly increased in hepatic fibrosis mice. At the same time, it was confirmed that activated hepatic stellate cells (HSCs) cocultured with M1 macrophages can promote their transformation into M2 macrophages in hepatic stellate cell line and primary hepatic stellate cells. In addition, the addition of lactic acid to the medium in which M1 cells are cultured can promote their transformation into M2 macrophages. Therefore, we concluded that activated HSCs can promote the transformation of M1 to M2 macrophages through lactate accumulation, thereby causing liver fibrosis.


Assuntos
Células Estreladas do Fígado , Histonas , Acetilação , Animais , Células Estreladas do Fígado/metabolismo , Histonas/metabolismo , Humanos , Ácido Láctico , Fígado/patologia , Cirrose Hepática/metabolismo , Macrófagos/metabolismo , Camundongos
10.
Biochemistry ; 61(18): 1974-1987, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36070615

RESUMO

Human lysine methyltransferase 2D (hKMT2D) is an epigenetic writer catalyzing the methylation of histone 3 lysine 4. hKMT2D by itself has little catalytic activity and reaches full activation as part of the WRAD2 complex, additionally comprising binding partners WDR5, RbBP5, Ash2L, and DPY30. Here, a detailed mechanistic study of the hKMT2D SET domain and its WRAD2 interactions is described. We characterized the WRAD2 subcomplexes containing full-length components and the hKMT2D SET domain. By performing steady-state analysis as a function of WRAD2 concentration, we identified the inner stoichiometry and determined the binding affinities for complex formation. Ash2L and RbBP5 were identified as the binding partners critical for the full catalytic activity of the SET domain. Contrary to a previous report, product and dead-end inhibitor studies identified hKMT2D as a rapid equilibrium random Bi-Bi mechanism with EAP and EBQ dead-end complexes. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF MS) analysis showed that hKMT2D uses a distributive mechanism and gives further insights into how the WRAD2 components affect mono-, di-, and trimethylation. We also conclude that the Win motif of hKMT2D is not essential in complex formation, unlike other hKMT2 proteins.


Assuntos
Histona-Lisina N-Metiltransferase , Lisina , Histona-Lisina N-Metiltransferase/química , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Lisina/metabolismo , Metilação , Proteína de Leucina Linfoide-Mieloide/química
11.
Proc Natl Acad Sci U S A ; 119(38): e2205691119, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36095189

RESUMO

The human Mixed Lineage Leukemia-1 (MLL1) complex methylates histone H3K4 to promote transcription and is stimulated by monoubiquitination of histone H2B. Recent structures of the MLL1-WRAD core complex, which comprises the MLL1 methyltransferase, WDR5, RbBp5, Ash2L, and DPY-30, have revealed variability in the docking of MLL1-WRAD on nucleosomes. In addition, portions of the Ash2L structure and the position of DPY30 remain ambiguous. We used an integrated approach combining cryoelectron microscopy (cryo-EM) and mass spectrometry cross-linking to determine a structure of the MLL1-WRAD complex bound to ubiquitinated nucleosomes. The resulting model contains the Ash2L intrinsically disordered region (IDR), SPRY insertion region, Sdc1-DPY30 interacting region (SDI-motif), and the DPY30 dimer. We also resolved three additional states of MLL1-WRAD lacking one or more subunits, which may reflect different steps in the assembly of MLL1-WRAD. The docking of subunits in all four states differs from structures of MLL1-WRAD bound to unmodified nucleosomes, suggesting that H2B-ubiquitin favors assembly of the active complex. Our results provide a more complete picture of MLL1-WRAD and the role of ubiquitin in promoting formation of the active methyltransferase complex.


Assuntos
Leucemia , Nucleossomos , Microscopia Crioeletrônica , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Ubiquitina/metabolismo
12.
Proc Natl Acad Sci U S A ; 119(38): e2207177119, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36103578

RESUMO

IMPORTIN-4, the primary nuclear import receptor of core histones H3 and H4, binds the H3-H4 dimer and histone chaperone ASF1 prior to nuclear import. However, how H3-H3-ASF1 is recognized for transport cannot be explained by available crystal structures of IMPORTIN-4-histone tail peptide complexes. Our 3.5-Å IMPORTIN-4-H3-H4-ASF1 cryoelectron microscopy structure reveals the full nuclear import complex and shows a binding mode different from suggested by previous structures. The N-terminal half of IMPORTIN-4 clamps the globular H3-H4 domain and H3 αN helix, while its C-terminal half binds the H3 N-terminal tail weakly; tail contribution to binding energy is negligible. ASF1 binds H3-H4 without contacting IMPORTIN-4. Together, ASF1 and IMPORTIN-4 shield nucleosomal H3-H4 surfaces to chaperone and import it into the nucleus where RanGTP binds IMPORTIN-4, causing large conformational changes to release H3-H4-ASF1. This work explains how full-length H3-H4 binds IMPORTIN-4 in the cytoplasm and how it is released in the nucleus.


Assuntos
Chaperonas de Histonas , Histonas , Proteínas de Ciclo Celular/metabolismo , Microscopia Crioeletrônica , Citoplasma/metabolismo , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Carioferinas/metabolismo
13.
Front Endocrinol (Lausanne) ; 13: 965445, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120466

RESUMO

Background: Hepatocellular carcinoma (HCC) is the third leading cause of death in the world, characterized by high morbidity, poor prognosis and high mortality. Histone modifications regulate intracellular gene expression at the post-transcriptional level, and disturbances in the regulatory pattern of histone modifications at individual locus or across the genome can lead to tumorigenesis of HCC. In this study, we constructed a prognosis-related histone phosphorylation regulated (HPR) genes signature and elucidated whether HPR genes can predict overall survival in HCC patients. Methods: Differentially expressed genes were screened using TCGA, ICGC and GEO databases, and a new risk signature was constructed by univariate Cox regression and Lasso regression analysis. Predictive nomograms were established by multivariate Cox regression of risk scores and clinical parameters, calibration curve and decision curve analysis were used to evaluate the models. The ssGSEA methods were used to determine the effect of risk scores on the tumor immune microenvironment. Data for HCC single-cell RNA sequencing (scRNA-seq) have been downloaded from Gene Expression Omnibus (GEO) to understand the role of HPR genes in tumorigenesis. Results: Our analyses of nine HPR genes provided prognostic insights. Overall survival in the low-risk and high-risk groups was statistically higher, respectively (P<0.001). Cox regression analysis revealed that the risk score is a significant predictor of HCC outcomes (HR=2. 2.62, 95%CI: 1.248-5.514, P=0.011). In addition, a nomogram combining risk scores with TNM stages was constructed and tested from calibration curves and decision curves (AUC=0.780). MHC-class-I genes, iDCs, Macrophages, Tfh, Treg, Th2 were overexpressed in the high-risk group. Conclusion: HPR genes risk score is closely related to the prognosis of HCC, tumor immune process and tumor cell progression.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/metabolismo , Carcinogênese , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Histonas/genética , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Fosforilação , Prognóstico , Análise de Sequência de RNA , Microambiente Tumoral/genética
14.
Nat Commun ; 13(1): 5447, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123357

RESUMO

Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to ERV de-repression in various cell types. However, it is currently not known if H3K9me3 and DNA methylation depend on each other for ERV silencing. Here we show that conditional knock-out of Setdb1 in mouse embryonic endoderm results in ERV de-repression in visceral endoderm (VE) descendants and does not occur in definitive endoderm (DE). Deletion of Setdb1 in VE progenitors results in loss of H3K9me3 and reduced DNA methylation of Intracisternal A-particle (IAP) elements, consistent with up-regulation of this ERV family. In DE, loss of Setdb1 does not affect H3K9me3 nor DNA methylation, suggesting Setdb1-independent pathways for maintaining these modifications. Importantly, Dnmt1 knock-out results in IAP de-repression in both visceral and definitive endoderm cells, while H3K9me3 is unaltered. Thus, our data suggest a dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm cells. Our findings suggest that Setdb1-meditated H3K9me3 is not sufficient for IAP silencing, but rather critical for maintaining high DNA methylation.


Assuntos
Metilação de DNA , Retrovirus Endógenos , Animais , Cromatina/metabolismo , DNA/metabolismo , Endoderma/metabolismo , Retrovirus Endógenos/metabolismo , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Camundongos
15.
Phys Rev E ; 106(2-1): 024408, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36110002

RESUMO

Nucleosomes are the fundamental building blocks of chromatin that not only help in the folding of chromatin, but also in carrying epigenetic information. It is known that nucleosome sliding is responsible for dynamically organizing chromatin structure and the resulting gene regulation. Since sliding can move two neighboring nucleosomes physically close or away, can it play a role in the spreading of histone modifications? We investigate this by simulating a stochastic model that couples nucleosome dynamics with the kinetics of histone modifications. We show that the sliding of nucleosomes can affect the modification pattern as well as the time it takes to modify a given region of chromatin. Exploring different nucleosome densities and modification kinetic parameters, we show that nucleosome sliding can be important for creating histone modification domains. Our model predicts that nucleosome density coupled with sliding dynamics can create an asymmetric histone modification profile around regulatory regions. We also compute the probability distribution of modified nucleosomes and relaxation kinetics of modifications. Our predictions are comparable with known experimental results.


Assuntos
Código das Histonas , Nucleossomos , Cromatina , Montagem e Desmontagem da Cromatina , Histonas/metabolismo
16.
Adv Exp Med Biol ; 1390: 277-293, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107325

RESUMO

The androgen receptor (AR) is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. As with other members of the NR family, transcriptional activity of the AR is regulated by interactions with coregulatory proteins, which either enhance (coactivators) or repress (corepressors) its transcriptional activity. AR associated coregulators are functionally diverse, but a large fraction are epigenetic histone and chromatin modifiers. Epigenetic coregulators are recruited to gene regulatory regions as part of multi-protein complexes, often acting in a dynamic and inter-dependent manner to remodel chromatin, thereby allowing or inhibiting the access of AR-associated transcriptional machinery to target genes; functional consequences being regulation of transcriptional output. Epigenetic modifiers, including those that function as AR coregulators, are frequently mutated or aberrantly expressed in prostate cancer and are implicated in disease progression. Some of these modifiers are being investigated as therapeutic targets in several cancer types and could potentially be used to modulate aberrant AR activity in prostate cancer. In this chapter we will summarise the functional role of epigenetic coregulators in AR signalling, their dysregulation during prostate cancer progression and the current status of drugs targeting these enzymes.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Cromatina , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Epigênese Genética , Histonas/genética , Histonas/metabolismo , Humanos , Ligantes , Masculino , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição/metabolismo
17.
Clin Epigenetics ; 14(1): 112, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068552

RESUMO

BACKGROUND: Despite clinical relevance of immunological activation due to histone leakage into the serum following cardiac surgery, long-term data describing their longitudinal dynamic are lacking. Therefore, this study examines the serum levels of histone 3 (tH3) and its modifications (H3K4me3 and H3K27ac) alongside immune system activation during the acute and convalescence phases of cardiac surgery. METHODS: Blood samples from fifty-nine individuals were collected before non-emergent cardiac surgery (tpre-op) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-procedure to examine serum levels of tH3, H3K4me3, and H3K27ac. Serum heat shock protein-60 (HSP-60) was a surrogate of the cellular damage marker. Serum C-reactive protein (CRP) and interleukin 6 (IL-6) assessed smoldering inflammation. TNFα and IL-6 production by whole blood in response to lipopolysaccharide (LPS) evaluated immunological activation. Electronic medical records provided demographic, peri-operative, and clinical information. Paired longitudinal analyses were employed with data expressed as mean and standard deviation (X ± SD) or median and interquartile range (Me[IQ25; 75%]. RESULTS: Compared to pre-operative levels (tH3Pre-op = 1.6[0.33;2.4]), post-operative serum tH3 significantly (p > 0.0001) increased after heart surgery (tH324hr = 2.2[0.3;28]), remained elevated at 7 days (tH37d = 2.4[0.37;5.3]), and at 3 months (tH33m = 2.0[0.31;2.9]). Serum H3K27ac was elevated at 24 h (H3K27ac24hr = 0.66 ± 0.51; p = 0.025) and seven days (H3K27ac7d = 0.94 ± 0.95; p = 0.032) as compared to baseline hours (H3K27acPre-op = 0.55 ± 0.54). Serum H3K4me3 was significantly diminished at three months (H3K4me3Pre-op = 0.94 ± 0.54 vs. H3K27ac3m = 0.59 ± 0.89; p = 0.008). tH3 correlated significantly with the duration of anesthesia (r2 = 0.38). In contrast, HSP-60 normalized seven days after surgery. Peri-operative intake of acetaminophen, but no acetylsalicylic acid (ASA), acid, ketorolac or steroids, resulted in the significant depression of serum H3K4me3 at 24 h (H3K4me3acetom- = 1.26[0.71; 3.21] vs H3K4me3acetom+ = 0.54[0.07;1.01]; W[50] = 2.26; p = 0.021). CRP, but not IL-6, remained elevated at 3 months compared to pre-surgical levels and correlated with tH324hrs (r2 = 0.43), tH37d (r2 = 0.71; p < 0.05), H3K4me37d (r2 = 0.53), and H3K27ac7d (r2 = 0.49). Production of TNFα by whole blood in response to LPS was associated with serum tH324hrs (r2 = 0.67). Diminished H3K4me324hrs, H3K27ac24hrs, and H3K27ac3m, accompanied the emergence of liver failure. CONCLUSIONS: We demonstrated a prolonged elevation in serum histone 3 three months after cardiac surgery. Furthermore, histone 3 modifications had a discrete time evolution indicating differential immune activation.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Histonas , Adulto , Proteína C-Reativa/metabolismo , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Metilação de DNA , Histonas/metabolismo , Humanos , Inflamação , Interleucina-6 , Lipopolissacarídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Signal Transduct Target Ther ; 7(1): 304, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050314

RESUMO

The occurrence of cancer entails a series of genetic mutations that favor uncontrollable tumor growth. It is believed that various factors collectively contribute to cancer, and there is no one single explanation for tumorigenesis. Epigenetic changes such as the dysregulation of enzymes modifying DNA or histones are actively involved in oncogenesis and inflammatory response. The methylation of lysine residues on histone proteins represents a class of post-translational modifications. The human Jumonji C domain-containing (JMJD) protein family consists of more than 30 members. The JMJD proteins have long been identified with histone lysine demethylases (KDM) and histone arginine demethylases activities and thus could function as epigenetic modulators in physiological processes and diseases. Importantly, growing evidence has demonstrated the aberrant expression of JMJD proteins in cancer and inflammatory diseases, which might serve as an underlying mechanism for the initiation and progression of such diseases. Here, we discuss the role of key JMJD proteins in cancer and inflammation, including the intensively studied histone lysine demethylases, as well as the understudied group of JMJD members. In particular, we focused on epigenetic changes induced by each JMJD member and summarized recent research progress evaluating their therapeutic potential for the treatment of cancer and inflammatory diseases.


Assuntos
Histona Desmetilases com o Domínio Jumonji , Neoplasias , Carcinogênese , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Inflamação/genética , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias/genética
19.
J Appl Oral Sci ; 30: e20220144, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36074434

RESUMO

OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is an oral cancer, with high malignancy and frequent early migration and invasion. Only a few drugs can treat tongue cancer. Ginsenoside Rd is a ginseng extract with anti-cancer effects. Many noncoding RNAs are abnormally expressed in tongue cancer, thus influencing its occurrence and development. H19 and miR-675-5p can promote cancer cell growth. This study aimed to analyze the regulation effect of ginsenoside Rd on H19 and miR-675-5p in tongue cancer. METHODOLOGY: We used CCK8 and flow cytometry to study the growth and apoptosis. Transwell assay was used to assess invasion; wound-healing assay to assess migration; and colony formation assays to test the ability of cells to form colonies. H19, miR-675-5p, and CDH1 expressions were analyzed by qPCR. E-cadherin expression was detected using western blot. CRISPR/cas9 system was used for CDH1 knockout. RESULTS: Ginsenoside Rd inhibited the growth and increased the apoptosis of SCC9 cells. Ginsenoside Rd also inhibited the migration and invasion of SCC9 cells. H19 and miR-675-5p were highly expressed, while CDH1 and E-cadherin expressions were low. H19 and miR-675-5p promoted SCC9 metastasis. In contrast, CDH1 and E-cadherin inhibited the metastasis of SCC9 cells. Bioinformatics analysis showed that miR-675-5p was associated with CDH1. H19 and miR-675-5p expressions decreased after ginsenoside Rd treatment, while CDH1 and E-cadherin expressions increased. CONCLUSIONS: Ginsenoside Rd inhibits tongue cancer cell migration and invasion via the H19/miR-675-5p/CDH1 axis.


Assuntos
Carcinoma de Células Escamosas , MicroRNAs , RNA Longo não Codificante , Neoplasias da Língua , Antígenos CD/farmacologia , Caderinas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ginsenosídeos , Histonas/metabolismo , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia , Língua/metabolismo , Neoplasias da Língua/tratamento farmacológico
20.
Sci Rep ; 12(1): 15636, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115870

RESUMO

Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders.


Assuntos
Montagem e Desmontagem da Cromatina , Histonas , Cromatina , Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Humanos , Interneurônios/metabolismo , Lisina/metabolismo , Neurogênese/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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