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1.
Anticancer Res ; 39(8): 4179-4184, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366503

RESUMO

BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2. MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells. RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 µM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 µM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells. CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.


Assuntos
Cumarínicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Código das Histonas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Metilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/genética
2.
Genome Biol ; 20(1): 139, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307500

RESUMO

BACKGROUND: Bread wheat is an allohexaploid species with a 16-Gb genome that has large intergenic regions, which presents a big challenge for pinpointing regulatory elements and further revealing the transcriptional regulatory mechanisms. Chromatin profiling to characterize the combinatorial patterns of chromatin signatures is a powerful means to detect functional elements and clarify regulatory activities in human studies. RESULTS: In the present study, through comprehensive analyses of the open chromatin, DNA methylome, seven major chromatin marks, and transcriptomic data generated for seedlings of allohexaploid wheat, we detected distinct chromatin architectural features surrounding various functional elements, including genes, promoters, enhancer-like elements, and transposons. Thousands of new genic regions and cis-regulatory elements are identified based on the combinatorial pattern of chromatin features. Roughly 1.5% of the genome encodes a subset of active regulatory elements, including promoters and enhancer-like elements, which are characterized by a high degree of chromatin openness and histone acetylation, an abundance of CpG islands, and low DNA methylation levels. A comparison across sub-genomes reveals that evolutionary selection on gene regulation is targeted at the sequence and chromatin feature levels. The divergent enrichment of cis-elements between enhancer-like sequences and promoters implies these functional elements are targeted by different transcription factors. CONCLUSIONS: We herein present a systematic epigenomic map for the annotation of cis-regulatory elements in the bread wheat genome, which provides new insights into the connections between chromatin modifications and cis-regulatory activities in allohexaploid wheat.


Assuntos
Montagem e Desmontagem da Cromatina , Metilação de DNA , Código das Histonas , Elementos Reguladores de Transcrição , Triticum/genética , Evolução Biológica , Epigenômica , Genoma de Planta , Plântula/metabolismo , Triticum/metabolismo
3.
BMC Bioinformatics ; 20(1): 401, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324140

RESUMO

BACKGROUND: Visualization tools for deep learning models typically focus on discovering key input features without considering how such low level features are combined in intermediate layers to make decisions. Moreover, many of these methods examine a network's response to specific input examples that may be insufficient to reveal the complexity of model decision making. RESULTS: We present DeepResolve, an analysis framework for deep convolutional models of genome function that visualizes how input features contribute individually and combinatorially to network decisions. Unlike other methods, DeepResolve does not depend upon the analysis of a predefined set of inputs. Rather, it uses gradient ascent to stochastically explore intermediate feature maps to 1) discover important features, 2) visualize their contribution and interaction patterns, and 3) analyze feature sharing across tasks that suggests shared biological mechanism. We demonstrate the visualization of decision making using our proposed method on deep neural networks trained on both experimental and synthetic data. DeepResolve is competitive with existing visualization tools in discovering key sequence features, and identifies certain negative features and non-additive feature interactions that are not easily observed with existing tools. It also recovers similarities between poorly correlated classes which are not observed by traditional methods. DeepResolve reveals that DeepSEA's learned decision structure is shared across genome annotations including histone marks, DNase hypersensitivity, and transcription factor binding. We identify groups of TFs that suggest known shared biological mechanism, and recover correlation between DNA hypersensitivities and TF/Chromatin marks. CONCLUSIONS: DeepResolve is capable of visualizing complex feature contribution patterns and feature interactions that contribute to decision making in genomic deep convolutional networks. It also recovers feature sharing and class similarities which suggest interesting biological mechanisms. DeepResolve is compatible with existing visualization tools and provides complementary insights.


Assuntos
Algoritmos , Aprendizado Profundo , Genômica , Redes Neurais (Computação) , Sequência de Bases , Bases de Dados Genéticas , Código das Histonas , Histonas/metabolismo , Fatores de Transcrição/metabolismo
4.
Nat Commun ; 10(1): 2529, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175278

RESUMO

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Ciclo Celular , Replicação do DNA , Regulação da Expressão Gênica , Histonas/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Neoplasias Encefálicas , Caenorhabditis elegans , Carcinogênese , Cromatina , Regulação Neoplásica da Expressão Gênica , Células Germinativas/metabolismo , Glioma , Heterocromatina , Código das Histonas , Metilação , Complexo Repressor Polycomb 2/metabolismo
5.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
6.
Genome Biol ; 20(1): 123, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208436

RESUMO

BACKGROUND: Cold stress can greatly affect plant growth and development. Plants have developed special systems to respond to and tolerate cold stress. While plant scientists have discovered numerous genes involved in responses to cold stress, few studies have been dedicated to investigation of genome-wide chromatin dynamics induced by cold or other abiotic stresses. RESULTS: Genomic regions containing active cis-regulatory DNA elements can be identified as DNase I hypersensitive sites (DHSs). We develop high-resolution DHS maps in potato (Solanum tuberosum) using chromatin isolated from tubers stored under room (22 °C) and cold (4 °C) conditions. We find that cold stress induces a large number of DHSs enriched in genic regions which are frequently associated with differential gene expression in response to temperature variation. Surprisingly, active genes show enhanced chromatin accessibility upon cold stress. A large number of active genes in cold-stored tubers are associated with the bivalent H3K4me3-H3K27me3 mark in gene body regions. Interestingly, upregulated genes associated with the bivalent mark are involved in stress response, whereas downregulated genes with the bivalent mark are involved in developmental processes. In addition, we observe that the bivalent mark-associated genes are more accessible than others upon cold stress. CONCLUSIONS: Collectively, our results suggest that cold stress induces enhanced chromatin accessibility and bivalent histone modifications of active genes. We hypothesize that in cold-stored tubers, the bivalent H3K4me3-H3K27me3 mark represents a distinct chromatin environment with greater accessibility, which may facilitate the access of regulatory proteins required for gene upregulation or downregulation in response to cold stress.


Assuntos
Montagem e Desmontagem da Cromatina , Resposta ao Choque Frio , Regulação da Expressão Gênica de Plantas , Código das Histonas , Solanum tuberosum/metabolismo , Desoxirribonuclease I/metabolismo , Histonas/metabolismo
7.
Genomics Proteomics Bioinformatics ; 17(2): 140-153, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31201999

RESUMO

Enhancers activate transcription in a distance-, orientation-, and position-independent manner, which makes them difficult to be identified. Self-transcribing active regulatory region sequencing (STARR-seq) measures the enhancer activity of millions of DNA fragments in parallel. Here we used STARR-seq to generate a quantitative global map of rice enhancers. Most enhancers were mapped within genes, especially at the 5' untranslated regions (5'UTR) and in coding sequences. Enhancers were also frequently mapped proximal to silent and lowly-expressed genes in transposable element (TE)-rich regions. Analysis of the epigenetic features of enhancers at their endogenous loci revealed that most enhancers do not co-localize with DNase I hypersensitive sites (DHSs) and lack the enhancer mark of histone modification H3K4me1. Clustering analysis of enhancers according to their epigenetic marks revealed that about 40% of identified enhancers carried one or more epigenetic marks. Repressive H3K27me3 was frequently enriched with positive marks, H3K4me3 and/or H3K27ac, which together label enhancers. Intergenic enhancers were also predicted based on the location of DHS regions relative to genes, which overlap poorly with STARR-seq enhancers. In summary, we quantitatively identified enhancers by functional analysis in the genome of rice, an important model plant. This work provides a valuable resource for further mechanistic studies in different biological contexts.


Assuntos
Elementos Facilitadores Genéticos , Genômica/métodos , Oryza/genética , Análise de Sequência de DNA , Transcrição Genética , Acetilação , Sequência de Bases , Desoxirribonuclease I/metabolismo , Epigênese Genética , Genes de Plantas , Código das Histonas/genética , Histonas/metabolismo , Modelos Genéticos , Regiões Promotoras Genéticas/genética , Sequências Repetitivas de Ácido Nucleico/genética
8.
J Biochem ; 166(1): 3-6, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31198932

RESUMO

Heterochromatin is a condensed and transcriptionally silent chromatin structure and that plays important roles in epigenetic regulation of the genome. Two types of heterochromatin exist: constitutive heterochromatin is primarily associated with trimethylation of histone H3 at lysine 9 (H3K9me3), and facultative heterochromatin with trimethylation of H3 at lysine 27 (H3K27me3). The methylated histones are bound by the chromodomain of histone code 'reader' proteins: HP1 family proteins for H3K9me3 and Polycomb family proteins for H3K27me3. Each repressive reader associates with various 'effector' proteins that provide the functional basis of heterochromatin. Heterochromatin regulation is primarily achieved by controlling histone modifications. However, recent studies have revealed that the repressive readers are phosphorylated, like other regulatory proteins, suggesting that phosphorylation also participates in heterochromatin regulation. Detailed studies have shown that phosphorylation of readers affects the binding specificities of chromodomains for methylated histone H3, as well as the binding of effector proteins. Thus, phosphorylation adds another layer to heterochromatin regulation. Interestingly, casein kinase 2, a strong and predominant kinase within the cell, is responsible for phosphorylation of repressive readers. In this commentary, I summarize the regulation of repressive readers by casein kinase 2-dependent phosphorylation and discuss the functional meaning of this modification.


Assuntos
Caseína Quinase II/metabolismo , Heterocromatina/metabolismo , Código das Histonas/fisiologia , Histonas/química , Histonas/metabolismo , Animais , Heterocromatina/química , Heterocromatina/genética , Histonas/genética , Humanos , Fosforilação
9.
PLoS Genet ; 15(6): e1008181, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31216276

RESUMO

The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic "scarring" of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.


Assuntos
Carcinoma Hepatocelular/genética , Epigênese Genética/genética , Hepacivirus/genética , Hepatite C/genética , Neoplasias Hepáticas/genética , Idoso , Antivirais/administração & dosagem , Biópsia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Cromatina/genética , Epigênese Genética/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Hepatite C/virologia , Código das Histonas/genética , Histonas/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Interferons/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resposta Viral Sustentada
10.
Int J Mol Sci ; 20(12)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200484

RESUMO

Ischemic penumbra that surrounds a stroke-induced infarction core is potentially salvageable; however, mechanisms of its formation are not well known. Covalent modifications of histones control chromatin conformation, gene expression and protein synthesis. To study epigenetic processes in ischemic penumbra, we used photothrombotic stroke (PTS), a stroke model in which laser irradiation of the rat brain cortex photosensitized by Rose Bengal induces local vessel occlusion. Immunoblotting and immunofluorescence microscopy showed decrease in acetylation of lysine 9 in histone H3 in penumbra at 1, 4 or 24 h after PTS. This was associated with upregulation of histone deacetylases HDAC1 and HDAC2, but not HDAC4, which did not localize in the nuclei. HDAC2 was found in cell nuclei, HDAC4 in the cytoplasm and HDAC1 both in nuclei and cytoplasm. Histone acetyltransferases HAT1 and PCAF (p300/CBP associated factor) that acetylated histone H3 synthesis were also upregulated, but lesser and later. PTS increased localization of HDAC2 and HAT1 in astroglia. Thus, the cell fate in PTS-induced penumbra is determined by the balance between opposite tendencies leading either to histone acetylation and stimulation of gene expression, or to deacetylation and suppression of transcriptional processes and protein biosynthesis. These epigenetic proteins may be the potential targets for anti-stroke therapy.


Assuntos
Córtex Cerebral/metabolismo , Epigênese Genética , Histona Acetiltransferases/metabolismo , Código das Histonas , Histona Desacetilases/metabolismo , Trombose Intracraniana/genética , Acidente Vascular Cerebral/genética , Acetilação , Animais , Histona Acetiltransferases/genética , Histona Desacetilases/genética , Histonas/genética , Histonas/metabolismo , Trombose Intracraniana/complicações , Trombose Intracraniana/metabolismo , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Regulação para Cima
11.
Nucleic Acids Res ; 47(10): 4911-4926, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162605

RESUMO

Histone modifications and RNA splicing, two seemingly unrelated gene regulatory processes, greatly increase proteome diversity and profoundly influence normal as well as pathological eukaryotic cellular functions. Like many histone modifying enzymes, histone deacetylases (HDACs) play critical roles in governing cellular behaviors and are indispensable in numerous biological processes. While the association between RNA splicing and histone modifications is beginning to be recognized, a lack of knowledge exists regarding the role of HDACs in splicing. Recent studies however, reveal that HDACs interact with spliceosomal and ribonucleoprotein complexes, actively control the acetylation states of splicing-associated histone marks and splicing factors, and thereby unexpectedly could modulate splicing. Here, we review the role of histone/protein modifications and HDACs in RNA splicing and discuss the convergence of two parallel fields, which supports the argument that HDACs, and perhaps most histone modifying enzymes, are much more versatile and far more complicated than their initially proposed functions. Analogously, an HDAC-RNA splicing connection suggests that splicing is regulated by additional upstream factors and pathways yet to be defined or not fully characterized. Some human diseases share common underlying causes of aberrant HDACs and dysregulated RNA splicing and, thus, further support the potential link between HDACs and RNA splicing.


Assuntos
Código das Histonas , Histona Desacetilases/metabolismo , Processamento de Proteína Pós-Traducional , Processamento de RNA , Humanos , Ligação Proteica , Ribonucleoproteínas/metabolismo , Spliceossomos/metabolismo , Transcrição Genética
12.
Plant Sci ; 284: 91-98, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31084884

RESUMO

Seeds germination or dormancy is strictly controlled by endogenous phytohormone signal and environment cues. High temperature (HT) suppresses seeds germination or triggers seeds dormancy but underlying mechanism by which HT mediates seeds germination thermoinhibition needs more investigating. SOM is reported as the critical factor negatively controls light-irradiation seeds germination by altering Abscisic acid (ABA) and gibberellin acid (GA) biosynthesis. Here we found that HT accelerates SOM expressing through ABA signal transduction component ABI3, both of abi3 and som mutants seeds show high germination rate under HT in contrast to wild type seeds. Using ABI3 as the bait, we identified the epigenetic factor Powerdress (PWR) as the ABI3 interaction protein. Genetic and physiological analysis showed that PWR negatively control the expressing of SOM, and overexpressing PWR enhanced, while pwr mutant reduced, seeds germination thermotolerance. Without HT stress, PWR accelerated the histone H3 deacetylation level and H2A.Z deposition at SOM locus, and thus suppressed ABI3-dependent SOM transcription for seeds germination, HT stress block PWR transcriptional level, thus attenuated the inhibition effect of PWR on SOM expressing, resulting into seeds germination thermoinhibition. Thus our finding propose a new function of PWR in controlling seeds germination under HT through histone acetylation modification and H2A.Z deposition.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Proteínas de Transporte/metabolismo , Germinação , Sementes/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/fisiologia , Proteínas de Transporte/fisiologia , Germinação/fisiologia , Resposta ao Choque Térmico , Código das Histonas , Plantas Geneticamente Modificadas , Sementes/metabolismo , Fatores de Transcrição/fisiologia , Técnicas do Sistema de Duplo-Híbrido
13.
Nat Commun ; 10(1): 1930, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036827

RESUMO

Many chromatin features play critical roles in regulating gene expression. A complete understanding of gene regulation will require the mapping of specific chromatin features in small samples of cells at high resolution. Here we describe Cleavage Under Targets and Tagmentation (CUT&Tag), an enzyme-tethering strategy that provides efficient high-resolution sequencing libraries for profiling diverse chromatin components. In CUT&Tag, a chromatin protein is bound in situ by a specific antibody, which then tethers a protein A-Tn5 transposase fusion protein. Activation of the transposase efficiently generates fragment libraries with high resolution and exceptionally low background. All steps from live cells to sequencing-ready libraries can be performed in a single tube on the benchtop or a microwell in a high-throughput pipeline, and the entire procedure can be performed in one day. We demonstrate the utility of CUT&Tag by profiling histone modifications, RNA Polymerase II and transcription factors on low cell numbers and single cells.


Assuntos
Cromatina/química , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Análise de Célula Única/métodos , Coloração e Rotulagem/métodos , Cromatina/metabolismo , Regulação da Expressão Gênica , Biblioteca Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Código das Histonas , Histonas/genética , Histonas/metabolismo , Humanos , Células K562 , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteína Estafilocócica A/genética , Proteína Estafilocócica A/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transposases/genética , Transposases/metabolismo
14.
Planta ; 250(2): 487-494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069521

RESUMO

MAIN CONCLUSION: Contrasting patterns of histone modifications between the X and Y chromosome in Silene latifolia show euchromatic histone mark depletion on the Y chromosome and indicate hyperactivation of one X chromosome in females. Silene latifolia (white campion) is a dioecious plant with heteromorphic sex chromosomes (24, XX in females and 24, XY in males), and a genetically degenerated Y chromosome that is 1.4 times larger than the X chromosome. Although the two sex chromosomes differ in their DNA content, information about epigenetic histone marks and evidence of their function are scarce. We performed immunolabeling experiments using antibodies specific for active and suppressive histone modifications as well as pericentromere-specific histone modifications. We show that the Y chromosome is partially depleted of histone modifications important for transcriptionally active chromatin, and carries these marks only in the pseudo-autosomal region, but that it is not enriched for suppressive and pericentromere histone marks. We also show that two of the active marks are specifically enriched in one of the X chromosomes in females and in the X chromosome in males. Our data support recent findings that genetic imprinting mediates dosage compensation of sex chromosomes in S. latifolia.


Assuntos
Cromossomos de Plantas/genética , Epigênese Genética , Código das Histonas/genética , Silene/genética
15.
Nat Commun ; 10(1): 2133, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086177

RESUMO

Polycomb (PcG) and Trithorax (TrxG) group proteins give stable epigenetic memory of silent and active gene expression states, but also allow poised states in pluripotent cells. Here we systematically address the relationship between poised, active and silent chromatin, by integrating 73 publications on PcG/TrxG biochemistry into a mathematical model comprising 144 nucleosome modification states and 8 enzymatic reactions. Our model predicts that poised chromatin is bistable and not bivalent. Bivalent chromatin, containing opposing active and silent modifications, is present as an unstable background population in all system states, and different subtypes co-occur with active and silent chromatin. In contrast, bistability, in which the system switches frequently between stable active and silent states, occurs under a wide range of conditions at the transition between monostable active and silent system states. By proposing that bistability and not bivalency is associated with poised chromatin, this work has implications for understanding the molecular nature of pluripotency.


Assuntos
Cromatina/metabolismo , Epigênese Genética/fisiologia , Modelos Biológicos , Proteínas do Grupo Polycomb/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Drosophila/metabolismo , Enzimas/metabolismo , Código das Histonas/fisiologia , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Nucleossomos/metabolismo
16.
Plant Cell Physiol ; 60(7): 1471-1486, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31038680

RESUMO

Chromatin accessibility and post-transcriptional histone modifications play important roles in gene expression regulation. However, little is known about the joint effect of multiple chromatin modifications on the gene expression level in plants, despite that the regulatory roles of individual histone marks such as H3K4me3 in gene expression have been well-documented. By using machine-learning methods, we systematically performed gene expression level prediction based on multiple chromatin modifications data in Arabidopsis and rice. We found that as few as four histone modifications were sufficient to yield good prediction performance, and H3K4me3 and H3K36me3 being the top two predictors with known functions related to transcriptional initiation and elongation, respectively. We demonstrated that the predictive powers differed between protein-coding and non-coding genes as well as between CpG-enriched and CpG-depleted genes. We also showed that the predictive model trained in one tissue or species could be applied to another tissue or species, suggesting shared underlying mechanisms. More interestingly, the gene expression levels of conserved orthologs are easier to predict than the species-specific genes. In addition, chromatin state of distal enhancers was moderately correlated to gene expression but was dispensable if given the chromatin features of the proximal regions of genes. We further extended the analysis to transcription factor (TF) binding data. Strikingly, the combinatorial effects of only a few TFs were roughly fit to gene expression levels in Arabidopsis. Overall, by using quantitative modeling, we provide a comprehensive and unbiased perspective on the epigenetic and TF-mediated regulation of gene expression in plants.


Assuntos
Cromatina/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Epigênese Genética , Código das Histonas , Oryza/metabolismo
17.
Nat Genet ; 51(5): 844-856, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31040401

RESUMO

The oocyte epigenome plays critical roles in mammalian gametogenesis and embryogenesis. Yet, how it is established remains elusive. Here, we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse oocyte epigenome. Deficiency in Setd2 leads to extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishing the correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories and aberrant acquisition of H3K4me3 at imprinting control regions instead of DNA methylation. Importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent one-cell arrest after fertilization. The preimplantation arrest is mainly due to a maternal cytosolic defect, since it can be largely rescued by normal oocyte cytosol. However, chromatin defects, including aberrant imprinting, persist in these embryos, leading to embryonic lethality after implantation. Thus, these data identify SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.


Assuntos
Desenvolvimento Embrionário/genética , Epigênese Genética , Impressão Genômica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Animais , DNA (Citosina-5-)-Metiltransferases/deficiência , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Feminino , Código das Histonas/genética , Histona-Lisina N-Metiltransferase/deficiência , Histonas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Genéticos , Oócitos/metabolismo , Oogênese/genética , Gravidez
18.
Nat Commun ; 10(1): 2226, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110221

RESUMO

Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.


Assuntos
Carcinogênese/genética , Polpa Dentária/citologia , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , PTEN Fosfo-Hidrolase/metabolismo , Adipócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Carcinogênese/patologia , Diferenciação Celular/genética , Células Cultivadas , Criança , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Polpa Dentária/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/metabolismo , Código das Histonas/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética , Análise de Sequência de RNA
19.
Artigo em Inglês | MEDLINE | ID: mdl-31079569

RESUMO

The purpose of this review is to highlight the impact of the alternative splicing process on human disease. Epigenetic regulation determines not only what parts of the genome are expressed but also how they are spliced. The recent progress in the field of epigenetics has important implications for the study of rare diseases. The role of epigenetics in rare diseases is a key issue in molecular physiology and medicine because not only rare diseases can benefit from epigenetic research, but can also provide useful principles for other common and complex disorders such as cancer, cardiovascular, type 2 diabetes, obesity, and neurological diseases. Predominantly, epigenetic modifications include DNA methylation, histone modification, and RNA-associated silencing. These modifications in the genome regulate numerous cellular activities. Disruption of epigenetic regulation process can contribute to the etiology of numerous diseases during both prenatal and postnatal life. Here, I discuss current knowledge about this matter including some current epigenetic therapies and future directions in the field by emphasizing on the RNA-based therapy via antisense oligonucleotides to correct splicing defects.


Assuntos
Epigênese Genética , Doenças Raras/genética , Doenças Raras/terapia , Processamento Alternativo , Animais , Metilação de DNA , Regulação da Expressão Gênica , Inativação Gênica , Código das Histonas , Humanos , Processamento de RNA
20.
PLoS Comput Biol ; 15(4): e1006982, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30986246

RESUMO

Hi-C and chromatin immunoprecipitation (ChIP) have been combined to identify long-range chromatin interactions genome-wide at reduced cost and enhanced resolution, but extracting information from the resulting datasets has been challenging. Here we describe a computational method, MAPS, Model-based Analysis of PLAC-seq and HiChIP, to process the data from such experiments and identify long-range chromatin interactions. MAPS adopts a zero-truncated Poisson regression framework to explicitly remove systematic biases in the PLAC-seq and HiChIP datasets, and then uses the normalized chromatin contact frequencies to identify significant chromatin interactions anchored at genomic regions bound by the protein of interest. MAPS shows superior performance over existing software tools in the analysis of chromatin interactions from multiple PLAC-seq and HiChIP datasets centered on different transcriptional factors and histone marks. MAPS is freely available at https://github.com/ijuric/MAPS.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , Cromatina/metabolismo , Cromatina/fisiologia , Imunoprecipitação da Cromatina/métodos , Simulação por Computador , Genoma , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Código das Histonas , Humanos , Análise de Sequência de DNA/métodos , Software
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