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1.
Nat Commun ; 11(1): 4703, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943643

RESUMO

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence, but their informativeness for human complex diseases is not fully understood. Here, we evaluate genome-wide SNP annotations from two previous deep learning models, DeepSEA and Basenji, by applying stratified LD score regression to 41 diseases and traits (average N = 320K), conditioning on a broad set of coding, conserved and regulatory annotations. We aggregated annotations across all (respectively blood or brain) tissues/cell-types in meta-analyses across all (respectively 11 blood or 8 brain) traits. The annotations were highly enriched for disease heritability, but produced only limited conditionally significant results: non-tissue-specific and brain-specific Basenji-H3K4me3 for all traits and brain traits respectively. We conclude that deep learning models have yet to achieve their full potential to provide considerable unique information for complex disease, and that their conditional informativeness for disease cannot be inferred from their accuracy in predicting regulatory annotations.


Assuntos
Aprendizado Profundo , Doença/genética , Anotação de Sequência Molecular , Alelos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/genética , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
Nat Commun ; 11(1): 4544, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917861

RESUMO

Stratification of enhancers by signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We examine a distinct method of stratification that focuses on peak breadth, termed hyperacetylated chromatin domains (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does using multiple data sets. Moreover, genetic manipulations of selected gene loci suggest that some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of histone modifications across domains and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.


Assuntos
Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Loci Gênicos/genética , Ativação Transcricional , Acetilação , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Sequenciamento de Cromatina por Imunoprecipitação , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Eritroblastos , Feminino , Feto , Código das Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , RNA-Seq
3.
Nat Commun ; 11(1): 4747, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958761

RESUMO

Chromosome structure at the multi-nucleosomal level has remained ambiguous in spite of its central role in epigenetic regulation and genome dynamics. Recent investigations of chromatin architecture portray diverse modes of interaction within and between nucleosome chains, but how this is realized at the atomic level is unclear. Here we present near-atomic resolution crystal structures of nucleosome fibres that assemble from cohesive-ended dinucleosomes with and without linker histone. As opposed to adopting folded helical '30 nm' structures, the fibres instead assume open zigzag conformations that are interdigitated with one another. Zigzag conformations obviate extreme bending of the linker DNA, while linker DNA size (nucleosome repeat length) dictates fibre configuration and thus fibre-fibre packing, which is supported by variable linker histone binding. This suggests that nucleosome chains have a predisposition to interdigitate with specific characteristics under condensing conditions, which rationalizes observations of local chromosome architecture and the general heterogeneity of chromatin structure.


Assuntos
Nucleossomos/química , Nucleossomos/metabolismo , Sequência de Bases , Cromatina/química , Cromatina/metabolismo , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica
4.
Mol Cell ; 79(3): 371-375, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32763226

RESUMO

Whereas the core nucleosome is thought to serve as a packaging device for the coiling and contraction in length of genomic DNA, we suggest that it serves primarily in the regulation of transcription. A nucleosome on a promoter prevents the initiation of transcription. The association of nucleosomes with most genomic DNA prevents initiation from cryptic promoters. The nucleosome thus serves not only as a general gene repressor, but also as a repressor of all transcription (genic, intragenic, and intergenic). The core nucleosome performs a fundamental regulatory role, apart from the histone "tails," which modulate gene activity.


Assuntos
Proteínas Cromossômicas não Histona/genética , Nucleossomos/metabolismo , RNA Polimerase II/genética , Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Transcrição Genética , Animais , Sítios de Ligação , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Evolução Molecular , Regulação da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Nucleossomos/ultraestrutura , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo
5.
Nat Commun ; 11(1): 4324, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859926

RESUMO

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Adolescente , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Estudos de Coortes , Glioma , Histonas/genética , Humanos , Leucócitos , Meduloblastoma/imunologia , Mutação , Prognóstico , Tumor Rabdoide
6.
Mol Cell ; 79(6): 934-949.e14, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32822587

RESUMO

Although ADP-ribosylation of histones by PARP-1 has been linked to genotoxic stress responses, its role in physiological processes and gene expression has remained elusive. We found that NAD+-dependent ADP-ribosylation of histone H2B-Glu35 by small nucleolar RNA (snoRNA)-activated PARP-1 inhibits AMP kinase-mediated phosphorylation of adjacent H2B-Ser36, which is required for the proadipogenic gene expression program. The activity of PARP-1 on H2B requires NMNAT-1, a nuclear NAD+ synthase, which directs PARP-1 catalytic activity to Glu and Asp residues. ADP-ribosylation of Glu35 and the subsequent reduction of H2B-Ser36 phosphorylation inhibits the differentiation of adipocyte precursors in cultured cells. Parp1 knockout in preadipocytes in a mouse lineage-tracing genetic model increases adipogenesis, leading to obesity. Collectively, our results demonstrate a functional interplay between H2B-Glu35 ADP-ribosylation and H2B-Ser36 phosphorylation that controls adipogenesis.


Assuntos
ADP-Ribosilação/genética , Adipogenia/genética , Histonas/genética , Poli(ADP-Ribose) Polimerase-1/genética , Adenosina Difosfato Ribose/genética , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Linhagem Celular , Dano ao DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Fosforilação/genética , RNA Nucleolar Pequeno/genética
7.
Proc Natl Acad Sci U S A ; 117(33): 19661-19663, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747537

RESUMO

The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A-H2B heterodimers and one histone (H3-H4)2 tetramer, wrapped around by ∼146 bp of DNA. The N-terminal flexible histone tails stick out from the histone core and have extensive posttranslational modifications, causing epigenetic changes of chromatin. Although crystal and cryogenic electron microscopy structures of nucleosomes are available, the flexible tail structures remain elusive. Using NMR, we have examined the dynamics of histone H3 tails in nucleosomes containing unmodified and tetra-acetylated H4 tails. In unmodified nucleosome, the H3 tail adopts a dynamic equilibrium structure between DNA-contact and reduced-contact states. In acetylated H4 nucleosome, however, the H3 tail equilibrium shifts to a mainly DNA-contact state with a minor reduced-contact state. The acetylated H4 tail is dynamically released from its own DNA-contact state to a reduced-contact state, while the H3 tail DNA-contact state becomes major. Notably, H3 K14 in the acetylated H4 nucleosome is much more accessible to acetyltransferase Gcn5 relative to unmodified nucleosome, possibly due to the formation of a favorable H3 tail conformation for Gcn5. In summary, each histone tail adopts a characteristic dynamic state but regulates one other, probably creating a histone tail network even on a nucleosome.


Assuntos
Histonas/química , Histonas/metabolismo , Nucleossomos/metabolismo , Acetilação , Motivos de Aminoácidos , DNA/genética , DNA/metabolismo , Histonas/genética , Humanos , Conformação de Ácido Nucleico , Nucleossomos/genética
8.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
9.
PLoS Genet ; 16(8): e1008962, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32750047

RESUMO

Haspin, a highly conserved kinase in eukaryotes, has been shown to be responsible for phosphorylation of histone H3 at threonine 3 (H3T3ph) during mitosis, in mammals and yeast. Here we report that haspin is the kinase that phosphorylates H3T3 in Drosophila melanogaster and it is involved in sister chromatid cohesion during mitosis. Our data reveal that haspin also phosphorylates H3T3 in interphase. H3T3ph localizes in broad silenced domains at heterochromatin and lamin-enriched euchromatic regions. Loss of haspin compromises insulator activity in enhancer-blocking assays and triggers a decrease in nuclear size that is accompanied by changes in nuclear envelope morphology. We show that haspin is a suppressor of position-effect variegation involved in heterochromatin organization. Our results also demonstrate that haspin is necessary for pairing-sensitive silencing and it is required for robust Polycomb-dependent homeotic gene silencing. Haspin associates with the cohesin complex in interphase, mediates Pds5 binding to chromatin and cooperates with Pds5-cohesin to modify Polycomb-dependent homeotic transformations. Therefore, this study uncovers an unanticipated role for haspin kinase in genome organization of interphase cells and demonstrates that haspin is required for homeotic gene regulation.


Assuntos
Cromatina/genética , Proteínas de Drosophila/genética , Mitose/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas de Ciclo Celular/genética , Centrômero/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Drosophila melanogaster/genética , Inativação Gênica , Heterocromatina/genética , Histonas/genética , Interfase/genética , Fosforilação , Proteínas do Grupo Polycomb/genética , Troca de Cromátide Irmã/genética , Treonina/genética
10.
PLoS Genet ; 16(8): e1008990, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810142

RESUMO

The kinetochore, a multi-protein complex assembled on centromeres, is essential to segregate chromosomes during cell division. Deficiencies in kinetochore function can lead to chromosomal instability and aneuploidy-a hallmark of cancer cells. Kinetochore function is controlled by recruitment of regulatory proteins, many of which have been documented, however their function often remains uncharacterized and many are yet to be identified. To identify candidates of kinetochore regulation we used a proteome-wide protein association strategy in budding yeast and detected many proteins that are involved in post-translational modifications such as kinases, phosphatases and histone modifiers. We focused on the Polo-like kinase, Cdc5, and interrogated which cellular components were sensitive to constitutive Cdc5 localization. The kinetochore is particularly sensitive to constitutive Cdc5 kinase activity. Targeting Cdc5 to different kinetochore subcomplexes produced diverse phenotypes, consistent with multiple distinct functions at the kinetochore. We show that targeting Cdc5 to the inner kinetochore, the constitutive centromere-associated network (CCAN), increases the levels of centromeric RNA via an SPT4 dependent mechanism.


Assuntos
Proteínas de Ciclo Celular/genética , Centrômero/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Elongação da Transcrição/genética , Anáfase/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Histonas/genética , Humanos , Cinetocoros/metabolismo , Mitose/genética , Fenótipo , Fosforilação/genética , RNA/genética , Saccharomyces cerevisiae/genética
11.
BMC Bioinformatics ; 21(1): 317, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32689977

RESUMO

BACKGROUND: The binding sites of transcription factors (TFs) and the localisation of histone modifications in the human genome can be quantified by the chromatin immunoprecipitation assay coupled with next-generation sequencing (ChIP-seq). The resulting chromatin feature data has been successfully adopted for genome-wide enhancer identification by several unsupervised and supervised machine learning methods. However, the current methods predict different numbers and different sets of enhancers for the same cell type and do not utilise the pattern of the ChIP-seq coverage profiles efficiently. RESULTS: In this work, we propose a PRobabilistic Enhancer PRedictIoN Tool (PREPRINT) that assumes characteristic coverage patterns of chromatin features at enhancers and employs a statistical model to account for their variability. PREPRINT defines probabilistic distance measures to quantify the similarity of the genomic query regions and the characteristic coverage patterns. The probabilistic scores of the enhancer and non-enhancer samples are utilised to train a kernel-based classifier. The performance of the method is demonstrated on ENCODE data for two cell lines. The predicted enhancers are computationally validated based on the transcriptional regulatory protein binding sites and compared to the predictions obtained by state-of-the-art methods. CONCLUSION: PREPRINT performs favorably to the state-of-the-art methods, especially when requiring the methods to predict a larger set of enhancers. PREPRINT generalises successfully to data from cell type not utilised for training, and often the PREPRINT performs better than the previous methods. The PREPRINT enhancers are less sensitive to the choice of prediction threshold. PREPRINT identifies biologically validated enhancers not predicted by the competing methods. The enhancers predicted by PREPRINT can aid the genome interpretation in functional genomics and clinical studies.


Assuntos
Cromatina/genética , Elementos Facilitadores Genéticos , Genoma Humano , Genômica/métodos , Histonas/genética , Modelos Estatísticos , Fatores de Transcrição/metabolismo , Cromatina/química , Cromatina/metabolismo , Código das Histonas , Histonas/química , Histonas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional
12.
Nat Commun ; 11(1): 3491, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661239

RESUMO

Sperm contributes genetic and epigenetic information to the embryo to efficiently support development. However, the mechanism underlying such developmental competence remains elusive. Here, we investigated whether all sperm cells have a common epigenetic configuration that primes transcriptional program for embryonic development. Using calibrated ChIP-seq, we show that remodelling of histones during spermiogenesis results in the retention of methylated histone H3 at the same genomic location in most sperm cell. This homogeneously methylated fraction of histone H3 in the sperm genome is maintained during early embryonic replication. Such methylated histone fraction resisting post-fertilisation reprogramming marks developmental genes whose expression is perturbed upon experimental reduction of histone methylation. A similar homogeneously methylated histone H3 fraction is detected in human sperm. Altogether, we uncover a conserved mechanism of paternal epigenetic information transmission to the embryo through the homogeneous retention of methylated histone in a sperm cells population.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Histonas/genética , Histonas/metabolismo , Masculino , Espermatogênese/genética , Espermatogênese/fisiologia , Xenopus
13.
Plant Mol Biol ; 104(1-2): 67-79, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621165

RESUMO

Acetylation and deacetylation of histones are important for regulating a series of biological processes in plants. Histone deacetylases (HDACs) control the histone deacetylation that plays an important role in plant response to abiotic stress. In our study, we show the evidence that GhHDT4D (a member of the HD2 subfamily of HDACs) is involved in cotton (Gossypium hirsutum) response to drought stress. Overexpression of GhHDT4D in Arabidopsis increased plant tolerance to drought, whereas silencing GhHDT4D in cotton resulted in plant sensitivity to drought. Simultaneously, the H3K9 acetylation level was altered in the GhHDT4D silenced cotton, compared with the controls. Further study revealed that GhHDT4D suppressed the transcription of GhWRKY33, which plays a negative role in cotton defense to drought, by reducing its H3K9 acetylation level. The expressions of the stress-related genes, such as GhDREB2A, GhDREB2C, GhSOS2, GhRD20-1, GhRD20-2 and GhRD29A, were significantly decreased in the GhHDT4D silenced cotton, but increased in the GhWRKY33 silenced cotton. Given these data together, our findings suggested that GhHDT4D may enhance drought tolerance by suppressing the expression of GhWRKY33, thereby activating the downstream drought response genes in cotton.


Assuntos
Secas , Gossypium/metabolismo , Histona Desacetilases/metabolismo , Estresse Fisiológico/fisiologia , Acetilação , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Gossypium/genética , Histona Desacetilases/genética , Histonas/genética , Histonas/metabolismo , Filogenia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Estresse Fisiológico/genética , Transcriptoma
14.
Plant Mol Biol ; 104(1-2): 113-136, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32627097

RESUMO

KEY MESSAGE: Present study revealed a complex relationship among histone H3 methylation (examined using H3K4/K27me3 marks), cytosine DNA methylation and differential gene expression during Lr28 mediated leaf rust resistance in wheat. During the present study, genome-wide histone modifications were examined in a pair of near isogenic lines (NILs) (with and without Lr28 in the background of cv. HD2329). The two histone marks used included H3K4me3 (an activation mark) and H3K27me3 (a repression mark). The results were compared with levels of expression (using RNA-seq) and DNA methylation (MeDIP) data obtained using the same pair of NILs. Some of the salient features of the present study include the following: (i) large scale differential binding sites (DBS) were available for only H3K4me3 in the susceptible cultivar, but for both H3K4me3 and H3K27me3 in its resistant NIL; (ii) DBSs for H3K27me3 mark were more abundant (> 80%) in intergenic regions, whereas DBSs for H3K4me3 were distributed in all genomic regions including exons, introns, intergenic, TTS (transcription termination sites) and promoters; (iii) fourteen (14) genes associated with DBSs showed co-localization for both the marks; (iv) only a small fraction (7% for H3K4me3 and 12% for H3K27me3) of genes associated with DBSs matched with the levels of gene expression inferred from RNA-seq data; (v) validation studies using qRT-PCR were conducted on 26 selected representative genes; results for only 11 genes could be validated. The proteins encoded by important genes involved in promoting infection included domains generally carried by R gene proteins such as Mlo like protein, protein kinases and purple acid phosphatase. Similarly, proteins encoded by genes involved in resistance included those carrying domains for lectin kinase, R gene, aspartyl protease, etc. Overall, the results suggest a very complex network of downstream genes that are expressed during compatible and incompatible interactions; some of the genes identified during the present study may be used in future validation studies involving RNAi/overexpression approaches.


Assuntos
Basidiomycota/metabolismo , Resistência à Doença/genética , Genes de Plantas/genética , Genoma de Planta/genética , Histonas/genética , Doenças das Plantas/genética , Triticum/genética , Triticum/metabolismo , Imunoprecipitação da Cromatina , Metilação de DNA , Regulação da Expressão Gênica de Plantas , Ligação Genética , Histonas/metabolismo , Anotação de Sequência Molecular , Doenças das Plantas/microbiologia , Folhas de Planta/genética , Folhas de Planta/microbiologia , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Alinhamento de Sequência , Análise de Sequência , Análise de Sequência de RNA , Transcrição Genética , Triticum/microbiologia
15.
PLoS Genet ; 16(7): e1008964, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716939

RESUMO

Chromatin regulation of eukaryotic genomes depends on the formation of nucleosome complexes between histone proteins and DNA. Histone variants, which are diversified by sequence or expression pattern, can profoundly alter chromatin properties. While variants in histone H2A and H3 families are well characterized, the extent of diversification of histone H2B proteins is less understood. Here, we report a systematic analysis of the histone H2B family in plants, which have undergone substantial divergence during the evolution of each major group in the plant kingdom. By characterising Arabidopsis H2Bs, we substantiate this diversification and reveal potential functional specialization that parallels the phylogenetic structure of emergent clades in eudicots. In addition, we identify a new class of highly divergent H2B variants, H2B.S, that specifically accumulate during chromatin compaction of dry seed embryos in multiple species of flowering plants. Our findings thus identify unsuspected diverse properties among histone H2B proteins in plants that has manifested into potentially novel groups of histone variants.


Assuntos
Arabidopsis/genética , Cromatina/genética , Evolução Molecular , Histonas/genética , Arabidopsis/classificação , Eucariotos , Genoma de Planta/genética , Histonas/classificação , Família Multigênica/genética
16.
Nat Commun ; 11(1): 3675, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699215

RESUMO

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/ß-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.


Assuntos
Biomarcadores Tumorais/genética , Epigênese Genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Idoso , Linhagem Celular Tumoral , Sequenciamento de Cromatina por Imunoprecipitação , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Conjuntos de Dados como Assunto , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Genômica , Heterocromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteômica , RNA-Seq , Sequenciamento Completo do Genoma
17.
Nat Commun ; 11(1): 3671, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699299

RESUMO

Epigenetic reprogramming is a cancer hallmark, but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We identify a dichotomy between bivalent genes that do and do not become hypermethylated, which is also mirrored in cancer. We find that loss of H3K4me3 at bivalent regions is associated with gain of methylation. Additionally, we observe that promoter CpG island hypermethylation is not restricted solely to emerging naïve cells, suggesting that it is a feature of a heterogeneous intermediate population during resetting. These results indicate that transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories, which implicates reprogramming and the pluripotency network as a central hub in cancer formation.


Assuntos
Transformação Celular Neoplásica/genética , Reprogramação Celular , Metilação de DNA , Epigênese Genética , Neoplasias/genética , Animais , Linhagem Celular , Técnicas de Cocultura , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Células-Tronco Embrionárias Humanas , Humanos , Camundongos , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/metabolismo
19.
PLoS One ; 15(7): e0235857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730263

RESUMO

OBJECTIVE: The risk loci for juvenile idiopathic arthritis (JIA) consist of extended haplotypes that include functional elements in addition to canonical coding genes. As with most autoimmune diseases, the risk haplotypes for JIA are highly enriched for H3K4me1/H3K27ac histone marks, epigenetic signatures that typically identify poised or active enhancers. In this study, we test the hypothesis that genetic risk for JIA is exerted through altered enhancer-mediated gene regulation. METHODS: We mined publically available HiC and other chromatin conformation data to determine whether H3K27ac-marked regions in 25 JIA risk loci showed physical evidence of contact with gene promoters. We also used in vitro reporter assays to establish as proof-of-concept the idea that genetic variants in linkage disequilibrium with GWAS-identified tag SNPs alter enhancer function. RESULTS: All 25 loci examined showed multiple contact sites in the 4 different cell lines that we queried. These regions were characterized by HiC-defined loop structures that included 237 immune-related genes. Using in vitro assays, we found that a 657 bp, H3K4me1/H3K27-marked region within the first intron of IL2RA shows enhancer activity in reporter assays, and this activity is attenuated by SNPs on the IL2RA haplotype that we identified using whole genome sequencing of children with JIA. Similarly, we identified a 1,669 bp sequence in an intergenic region of the IL6R locus where SNPs identified in children with JIA increase enhancer function in reporter assays. CONCLUSIONS: These studies provide evidence that altered enhancer function contributes to genetic risk in JIA. Further studies to identify the specific target genes of genetically altered enhancers are warranted.


Assuntos
Artrite Juvenil/genética , Montagem e Desmontagem da Cromatina , Elementos Facilitadores Genéticos , Histonas/genética , Polimorfismo de Nucleotídeo Único , Humanos , Células K562 , Locos de Características Quantitativas , Células THP-1
20.
PLoS One ; 15(7): e0235705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649682

RESUMO

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.


Assuntos
Antineoplásicos/farmacologia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Linfócitos T/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Interferons/farmacologia , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo
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