Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.391
Filtrar
1.
Mem Inst Oswaldo Cruz ; 115: e190457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428081

RESUMO

BACKGROUND Imitation SWItch (ISWI) ATPase is the catalytic subunit in diverse chromatin remodeling complexes. These complexes modify histone-DNA interactions and therefore play a pivotal role in different DNA-dependent processes. In Trypanosoma cruzi, a protozoan that controls gene expression principally post-transcriptionally, the transcriptional regulation mechanisms mediated by chromatin remodeling are poorly understood. OBJECTIVE To characterise the ISWI remodeler in T. cruzi (TcISWI). METHODS A new version of pTcGW vectors was constructed to express green fluorescent protein (GFP)-tagged TcISWI. CRISPR-Cas9 system was used to obtain parasites with inactivated TcISWI gene and we determined TcISWI partners by cryomilling-affinity purification-mass spectrometry (MS) assay as an approximation to start to unravel the function of this protein. FINDINGS Our approach identified known ISWI partners [nucleoplasmin-like protein (NLP), regulator of chromosome condensation 1-like protein (RCCP) and phenylalanine/tyrosine-rich protein (FYRP)], previously characterised in T. brucei, and new components in TcISWI complex [DRBD2, DHH1 and proteins containing a domain characteristic of structural maintenance of chromosomes (SMC) proteins]. Data are available via ProteomeXchange with identifier PXD017869. MAIN CONCLUSIONS In addition to its participation in transcriptional silencing, as it was reported in T. brucei, the data generated here provide a framework that suggests a role for TcISWI chromatin remodeler in different nuclear processes in T. cruzi, including mRNA nuclear export control and chromatin compaction. Further work is necessary to clarify the TcISWI functional diversity that arises from this protein interaction study.


Assuntos
Adenosina Trifosfatases/genética , Montagem e Desmontagem da Cromatina/genética , Fatores de Transcrição/genética , Trypanosoma cruzi/genética , Animais , Western Blotting , Citometria de Fluxo , Regulação da Expressão Gênica
2.
Gene ; 742: 144577, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171825

RESUMO

Gastric cancer is a complex heterogeneous disease which is the fourth prevalent malignancy worldwide. Although, several diagnosis and treatment are available for the gastric cancer patients, however the malignancy is still the third leading cause of cancer-related death in the world. Beside the genetic and environmental factors, epigenetic alterations are also involved in the emergence of gastric cancer. Epigenetics alterations are heritable changes which regulate gene expression without occurring changes in DNA sequence. Epigenetic changes mostly include DNA methylation, histon post-translational modifications, chromatin remodeling and non-coding RNAs. Among the mentioned epigenetic modifications, DNA methylation is a major epigenetic process that plays a key role in different stages of evolution and cancer development. In this review, we address all types of related epigenetic modifications in gastric cancer by focus on DNA methylation by reviewing the recent literatures. Understanding of molecular mechanisms of epigenetics alterations in gastric cancer development helps researchers to identify new epigenetic drugs against the malignancy.


Assuntos
Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Montagem e Desmontagem da Cromatina/genética , Código das Histonas/genética , Humanos , RNA não Traduzido/genética , Neoplasias Gástricas/patologia
3.
PLoS Genet ; 16(3): e1008543, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32134927

RESUMO

Following fertilization of a mature oocyte, the formation of a diploid zygote involves a series of coordinated cellular events that ends with the first embryonic mitosis. In animals, this complex developmental transition is almost entirely controlled by maternal gene products. How such a crucial transcriptional program is established during oogenesis remains poorly understood. Here, we have performed an shRNA-based genetic screen in Drosophila to identify genes required to form a diploid zygote. We found that the Lid/KDM5 histone demethylase and its partner, the Sin3A-HDAC1 deacetylase complex, are necessary for sperm nuclear decompaction and karyogamy. Surprisingly, transcriptomic analyses revealed that these histone modifiers are required for the massive transcriptional activation of deadhead (dhd), which encodes a maternal thioredoxin involved in sperm chromatin remodeling. Unexpectedly, while lid knock-down tends to slightly favor the accumulation of its target, H3K4me3, on the genome, this mark was lost at the dhd locus. We propose that Lid/KDM5 and Sin3A cooperate to establish a local chromatin environment facilitating the unusually high expression of dhd, a key effector of the oocyte-to-zygote transition.


Assuntos
Proteínas de Drosophila/genética , Histona Desmetilases/genética , Oócitos/fisiologia , Zigoto/fisiologia , Animais , Núcleo Celular/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Drosophila/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/genética , Masculino , Oogênese/genética , Espermatozoides/fisiologia , Transcrição Genética/genética
4.
Nat Genet ; 52(3): 273-282, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32139906

RESUMO

Mutations in enzymes that modify histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) have been linked to human disease, yet the role of these residues in mammals is unclear. We mutated K4 or K36 to alanine in the histone variant H3.3 and showed that the K4A mutation in mouse embryonic stem cells (ESCs) impaired differentiation and induced widespread gene expression changes. K4A resulted in substantial H3.3 depletion, especially at ESC promoters; it was accompanied by reduced remodeler binding and increased RNA polymerase II (Pol II) activity. Regulatory regions depleted of H3.3K4A showed histone modification alterations and changes in enhancer activity that correlated with gene expression. In contrast, the K36A mutation did not alter H3.3 deposition and affected gene expression at the later stages of differentiation. Thus, H3K4 is required for nucleosome deposition, histone turnover and chromatin remodeler binding at regulatory regions, where tight regulation of Pol II activity is necessary for proper ESC differentiation.


Assuntos
Diferenciação Celular/genética , Montagem e Desmontagem da Cromatina/genética , Código das Histonas/genética , Histonas/genética , Lisina/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Alanina/metabolismo , Animais , Elementos Facilitadores Genéticos/genética , Células HEK293 , Humanos , Camundongos , Células-Tronco Embrionárias Murinas , Mutação , Nucleossomos/metabolismo , Regiões Promotoras Genéticas/genética , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transcrição Genética
5.
Nat Rev Mol Cell Biol ; 21(3): 137-150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020082

RESUMO

Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes.


Assuntos
Envelhecimento/genética , Epigênese Genética/genética , Rejuvenescimento/fisiologia , Animais , Montagem e Desmontagem da Cromatina/genética , Metilação de DNA/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Código das Histonas/genética , Humanos , Longevidade/genética
6.
Nat Rev Mol Cell Biol ; 21(3): 123-136, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020081

RESUMO

Much of the mammalian genome is transcribed, generating long non-coding RNAs (lncRNAs) that can undergo post-transcriptional surveillance whereby only a subset of the non-coding transcripts is allowed to attain sufficient stability to persist in the cellular milieu and control various cellular functions. Paralleling protein turnover by the proteasome complex, lncRNAs are also likely to exist in a dynamic equilibrium that is maintained through constant monitoring by the RNA surveillance machinery. In this Review, we describe the RNA surveillance factors and discuss the vital role of lncRNA surveillance in orchestrating various biological processes, including the protection of genome integrity, maintenance of pluripotency of embryonic stem cells, antibody-gene diversification, coordination of immune cell activation and regulation of heterochromatin formation. We also discuss examples of human diseases and developmental defects associated with the failure of RNA surveillance mechanisms, further highlighting the importance of lncRNA surveillance in maintaining cell and organism functions and health.


Assuntos
Regulação da Expressão Gênica/genética , Estabilidade de RNA/fisiologia , RNA Longo não Codificante/genética , Animais , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Genoma/genética , Humanos , Estabilidade de RNA/genética , RNA Longo não Codificante/metabolismo
7.
Nat Commun ; 11(1): 1018, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094342

RESUMO

Mammalian genomes encode tens of thousands of noncoding RNAs. Most noncoding transcripts exhibit nuclear localization and several have been shown to play a role in the regulation of gene expression and chromatin remodeling. To investigate the function of such RNAs, methods to massively map the genomic interacting sites of multiple transcripts have been developed; however, these methods have some limitations. Here, we introduce RNA And DNA Interacting Complexes Ligated and sequenced (RADICL-seq), a technology that maps genome-wide RNA-chromatin interactions in intact nuclei. RADICL-seq is a proximity ligation-based methodology that reduces the bias for nascent transcription, while increasing genomic coverage and unique mapping rate efficiency compared with existing methods. RADICL-seq identifies distinct patterns of genome occupancy for different classes of transcripts as well as cell type-specific RNA-chromatin interactions, and highlights the role of transcription in the establishment of chromatin structure.


Assuntos
Cromatina/metabolismo , Mapeamento Cromossômico/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA não Traduzido/genética , Análise de Sequência de RNA/métodos , Animais , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Biblioteca Gênica , Camundongos , Células-Tronco Embrionárias Murinas , RNA não Traduzido/metabolismo , Transcrição Genética
8.
PLoS One ; 15(2): e0229103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053677

RESUMO

Chemical modifications that regulate protein expression at the translational level are emerging as vital components of the cellular stress response. Transfer RNAs (tRNAs) are significant targets for methyl-based modifications, which are catalyzed by tRNA methyltransferases (Trms). Here, Saccharomyces cerevisiae served as a model eukaryote system to investigate the role of 2'-O-ribose tRNA methylation in the cell's response to oxidative stress. Using 2'-O-ribose deletion mutants for trms 3, 7, 13, and 44, in acute and chronic exposure settings, we demonstrate a broad cell sensitivity to oxidative stress-inducing toxicants (i.e., hydrogen peroxide, rotenone, and acetic acid). A global analysis of hydrogen peroxide-induced tRNA modifications shows a complex profile of decreased, or undetectable, 2'-O-ribose modification events in 2'-O-ribose trm mutant strains, providing a critical link between this type of modification event and Trm status post-exposure. Based on the pronounced oxidative stress sensitivity observed for trm7 mutants, we used a bioinformatic tool to identify transcripts as candidates for regulation by Trm7-catalyzed modifications (i.e., enriched in UUC codons decoded by tRNAPheGmAA). This screen identified transcripts linked to diverse biological processes that promote cellular recovery after oxidative stress exposure, including DNA repair, chromatin remodeling, and nutrient acquisition (i.e., CRT10, HIR3, HXT2, and GNP1); moreover, these mutants were also oxidative stress-sensitive. Together, these results solidify a role for TRM3, 7, 13, and 44, in the cellular response to oxidative stress, and implicate 2'-O-ribose tRNA modification as an epitranscriptomic strategy for oxidative stress recovery.


Assuntos
RNA de Transferência/metabolismo , Ribose/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Reparo do DNA/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , tRNA Metiltransferases/genética , tRNA Metiltransferases/metabolismo
9.
Parasit Vectors ; 13(1): 48, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019597

RESUMO

BACKGROUND: Various transcription factors are involved in the process of mutually exclusive expression and clonal variation of the Plasmodium multigene (var) family. Recent studies revealed that a P. falciparum SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (PfSWIB) might trigger stage-specific programmed cell death (PCD), and was not only crucial for the survival and development of parasite, but also had profound effects on the parasite by interacting with other unknown proteins. However, it remains unclear whether PfSIWB is involved in transcriptional regulation of this virulence gene and its functional properties. METHODS: A conditional knockdown system "PfSWIB-FKBP-LID" was introduced to the parasite clone 3D7, and an integrated parasite line "PfSWIB-HA-FKBP-LID" was obtained by drug cycling and clone screening. Growth curve analysis (GCA) was performed to investigate the growth and development of different parasite lines during 96 h in vitro culturing, by assessing parasitemia. Finally, we performed qPCR assays to detect var gene expression profiling in various comparison groups, as well as the mutually exclusive expression pattern of the var genes within a single 48 h life-cycle of P. falciparum in different parasite lines. In addition, RNA-seq was applied to analyze the var gene expression in different lines. RESULTS: GCA revealed that conditional knockdown of PfSWIB could interfere with the growth and development of P. falciparum. The parasitemia of PfSWIB∆ showed a significant decline at 96 h during in vitro culture compared with the PfSWIB and 3D7 lines (P < 0.0001). qPCR and RNA-seq analysis confirmed that depletion of PfSWIB not only silences upsA, upsC and partial upsB var genes, as well as removes the silencing of partial upsB var genes at the ring stage in PfSWIB∆ line, but also leads to aberrant expression of upsA and partial upsB/upsC var genes at the mature stage of P. falciparum, during a single 48-h life-cycle. CONCLUSIONS: We demonstrated that PfSWIB was involved in the process of clonal variation in var gene expression, and crucial for the survival and development of Plasmodium parasite. These findings could provide better understanding of the mechanism and function of PfSWIB contributing to the pathogenesis in malaria parasites.


Assuntos
Plasmodium falciparum/genética , Proteínas de Protozoários/metabolismo , Montagem e Desmontagem da Cromatina/genética , Eritrócitos/parasitologia , Regulação da Expressão Gênica , Inativação Gênica , Genes de Protozoários , Humanos , Estágios do Ciclo de Vida/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/genética , Fatores de Virulência/genética
10.
Cancer Sci ; 111(3): 1008-1019, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922331

RESUMO

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.


Assuntos
Adenocarcinoma/genética , Montagem e Desmontagem da Cromatina/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos
11.
Nucleic Acids Res ; 48(6): 2912-2923, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-31970414

RESUMO

NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-ß signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-ß signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-ß signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-ß signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-ß signaling related diseases.


Assuntos
Movimento Celular , Histona Desacetilases/metabolismo , Proteínas Repressoras/metabolismo , Sirtuínas/metabolismo , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Montagem e Desmontagem da Cromatina/genética , Resistencia a Medicamentos Antineoplásicos/genética , Células HEK293 , Humanos , Metástase Neoplásica , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Repressoras/antagonistas & inibidores , Transdução de Sinais , Sirtuínas/genética , Transcrição Genética , Fator de Crescimento Transformador beta/metabolismo
12.
Bull Cancer ; 107(1): 41-47, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31916995

RESUMO

A growing number of studies suggest a tumor suppressor role for the SWI/SNF complex involved in the remodeling of chromatin. Alterations of this complex have been found in many tumors of different origins, with topographic, morphologic and phenotypic diversity. Notably, they define 2 types of thoracic tumors: SMARCA4-deficient non-small cell lung carcinoma and SMARCA4-deficient sarcoma. Some clinical features appear to be common to both, such as intrathoracic localization, smoking exposure, male predominance and poor prognosis. However, the histological distinction between these two entities is sometimes difficult and it is not excluded that these entities belong to the same tumor spectrum with different degrees of differentiation. The therapy of these tumors is not yet codified. These tumors do not seem associated with oncogenic driver mutations allowing the prescription of targeted therapy, but immunotherapy has been shown to be effective in rare reported cases. More specific treatments using EZH2 inhibitors also seem promising in SMARCA4 deficient sarcomas.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Montagem e Desmontagem da Cromatina , DNA Helicases/deficiência , Proteínas de Neoplasias/deficiência , Proteínas Nucleares/deficiência , Sarcoma/genética , Neoplasias Torácicas/genética , Fatores de Transcrição/deficiência , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , DNA Helicases/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Terapia de Alvo Molecular , Complexos Multiproteicos/efeitos dos fármacos , Complexos Multiproteicos/fisiologia , Invasividade Neoplásica , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/fisiologia , Proteína SMARCB1/fisiologia , Sarcoma/patologia , Sarcoma/terapia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/terapia , Fatores de Transcrição/fisiologia
13.
BMC Med Genet ; 21(1): 10, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914951

RESUMO

BACKGROUND: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.


Assuntos
Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Fenótipo , Esquizofrenia/fisiopatologia , Convulsões Febris/genética , Convulsões Febris/patologia
14.
Nat Genet ; 52(1): 8-16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31925403

RESUMO

Genomes across a wide range of eukaryotic organisms fold into higher-order chromatin domains. Topologically associating domains (TADs) were originally discovered empirically in low-resolution Hi-C heat maps representing ensemble average interaction frequencies from millions of cells. Here, we discuss recent advances in high-resolution Hi-C, single-cell imaging experiments, and functional genetic studies, which provide an increasingly complex view of the genome's hierarchical structure-function relationship. On the basis of these new findings, we update the definitions of distinct classes of chromatin domains according to emerging knowledge of their structural, mechanistic and functional properties.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica , Genoma , Transcrição Genética , Animais , Compartimento Celular , Humanos , Modelos Biológicos
15.
Science ; 367(6476)2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974223

RESUMO

Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Cromatina/metabolismo , Neurogênese , Prosencéfalo/embriologia , Animais , Linhagem da Célula , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transtornos Mentais/embriologia , Transtornos Mentais/genética , Camundongos , Doenças do Sistema Nervoso/embriologia , Doenças do Sistema Nervoso/genética , Organoides/embriologia , Células-Tronco Pluripotentes/fisiologia , Transcriptoma
16.
Cell Mol Life Sci ; 77(5): 807-818, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897542

RESUMO

The study of epigenetics has explained some of the 'missing heritability' of age-related macular degeneration (AMD). The epigenome also provides a substantial contribution to the organisation of the functional retina. There is emerging evidence of specific epigenetic mechanisms associated with AMD. This 'AMD epigenome' may offer the chance to develop novel AMD treatments.


Assuntos
Epigênese Genética/genética , Predisposição Genética para Doença/genética , Degeneração Macular/genética , Retina/patologia , Montagem e Desmontagem da Cromatina/genética , Metilação de DNA/genética , Genoma Humano/genética , Humanos , MicroRNAs/genética , Retina/citologia , Fatores de Risco
17.
Genes Dev ; 34(3-4): 166-178, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31919188

RESUMO

Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of Snf2h are infertile and oocytes lacking Snf2h fail to undergo meiotic resumption. Mechanistically, depletion of Snf2h results in dysregulation of meiosis-related genes, which causes failure of maturation-promoting factor (MPF) activation. ATAC-seq analysis in oocytes revealed that Snf2h regulates transcription of key meiotic genes, such as Prkar2b, by increasing its promoter chromatin accessibility. Thus, our studies not only demonstrate the importance of Snf2h in oocyte meiotic resumption, but also reveal the mechanism underlying how a chromatin remodeling factor can regulate oocyte meiosis.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Montagem e Desmontagem da Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Fator Promotor de Maturação/genética , Meiose/genética , Oogênese/genética , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Camundongos , Oócitos/citologia , Transcriptoma
18.
Cancer Sci ; 111(3): 774-782, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31955490

RESUMO

The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss-of-function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/genética , Neoplasias/genética , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos
19.
Nucleic Acids Res ; 48(3): 1531-1550, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31807785

RESUMO

FKBP53 is one of the seven multi-domain FK506-binding proteins present in Arabidopsis thaliana, and it is known to get targeted to the nucleus. It has a conserved PPIase domain at the C-terminus and a highly charged N-terminal stretch, which has been reported to bind to histone H3 and perform the function of a histone chaperone. To better understand the molecular details of this PPIase with histone chaperoning activity, we have solved the crystal structures of its terminal domains and functionally characterized them. The C-terminal domain showed strong PPIase activity, no role in histone chaperoning and revealed a monomeric five-beta palm-like fold that wrapped over a helix, typical of an FK506-binding domain. The N-terminal domain had a pentameric nucleoplasmin-fold; making this the first report of a plant nucleoplasmin structure. Further characterization revealed the N-terminal nucleoplasmin domain to interact with H2A/H2B and H3/H4 histone oligomers, individually, as well as simultaneously, suggesting two different binding sites for H2A/H2B and H3/H4. The pentameric domain assists nucleosome assembly and forms a discrete complex with pre-formed nucleosomes; wherein two pentamers bind to a nucleosome.


Assuntos
Proteínas de Arabidopsis/ultraestrutura , Histonas/genética , Chaperonas Moleculares/ultraestrutura , Nucleoplasminas/química , Proteínas de Ligação a Tacrolimo/ultraestrutura , Arabidopsis/química , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Sítios de Ligação/genética , Montagem e Desmontagem da Cromatina/genética , Cristalografia por Raios X , Histonas/química , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Nucleoplasminas/genética , Nucleossomos/química , Nucleossomos/genética , Peptidilprolil Isomerase/genética , Ligação Proteica/genética , Domínios Proteicos/genética , Dobramento de Proteína , Proteínas de Ligação a Tacrolimo/química , Proteínas de Ligação a Tacrolimo/genética
20.
Mol Cell ; 77(2): 395-410.e3, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31759824

RESUMO

The recovery of stalled replication forks depends on the controlled resection of nascent DNA and on the loading of cohesin. These processes operate in the context of nascent chromatin, but the impact of nucleosome structure on a fork restart remains poorly understood. Here, we show that the Mre11-Rad50-Xrs2 (MRX) complex acts together with the chromatin modifiers Gcn5 and Set1 and the histone remodelers RSC, Chd1, and Isw1 to promote chromatin remodeling at stalled forks. Increased chromatin accessibility facilitates the resection of nascent DNA by the Exo1 nuclease and the Sgs1 and Chl1 DNA helicases. Importantly, increased ssDNA promotes the recruitment of cohesin to arrested forks in a Scc2-Scc4-dependent manner. Altogether, these results indicate that MRX cooperates with chromatin modifiers to orchestrate the action of remodelers, nucleases, and DNA helicases, promoting the resection of nascent DNA and the loading of cohesin, two key processes involved in the recovery of arrested forks.


Assuntos
Proteínas de Ciclo Celular/genética , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/genética , Replicação do DNA/genética , DNA Fúngico/genética , Proteínas de Ligação a DNA/genética , Endodesoxirribonucleases/genética , Exodesoxirribonucleases/genética , Proteínas de Saccharomyces cerevisiae/genética , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Nucleossomos/genética , RecQ Helicases/genética , Saccharomyces cerevisiae/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA