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1.
Nat Cell Biol ; 26(5): 770-783, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38600236

RESUMO

DNA-protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such as replication, which is counteracted through proteolysis-mediated DPC removal by spartan (SPRTN) or the proteasome. However, whether DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here we show that DPCs severely impede RNA polymerase II-mediated transcription and are preferentially repaired in active genes by transcription-coupled DPC (TC-DPC) repair. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymerase II. CSA and CSB are indispensable for TC-DPC repair; however, the downstream TC-NER factors UVSSA and XPA are not, a result indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription.


Assuntos
DNA Helicases , Enzimas Reparadoras do DNA , Reparo do DNA , Proteínas de Ligação a Poli-ADP-Ribose , Proteólise , RNA Polimerase II , Transcrição Gênica , Humanos , Proteínas de Transporte , DNA/metabolismo , DNA/genética , Dano ao DNA , DNA Helicases/metabolismo , DNA Helicases/genética , Enzimas Reparadoras do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células HEK293 , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Interleucina-17 , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
2.
Front Cell Neurosci ; 17: 1114420, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37082206

RESUMO

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.

4.
Front Neurosci ; 16: 846272, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35615272

RESUMO

Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

6.
Nat Commun ; 10(1): 2669, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209209

RESUMO

The Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density defines super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here, we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein interaction partners. We identify super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalize with Mediator at enhancers and super enhancers. Transcription factor families with high affinity for Mediator dominate enhancers and super enhancers and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator of NSCs. Tcf4 interacts with Mediator, colocalizes with Mediator at super enhancers and regulates neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Redes Reguladoras de Genes/fisiologia , Complexo Mediador/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Fator de Transcrição 4/metabolismo , Linhagem Celular , Elementos Facilitadores Genéticos/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Regiões Promotoras Genéticas/genética , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Transcrição Gênica/fisiologia
8.
Neuron ; 93(2): 348-361, 2017 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-28041881

RESUMO

Mutations in NIPBL are the most frequent cause of Cornelia de Lange syndrome (CdLS), a developmental disorder encompassing several neurological defects, including intellectual disability and seizures. How NIPBL mutations affect brain development is not understood. Here we identify Nipbl as a functional interaction partner of the neural transcription factor Zfp609 in brain development. Depletion of Zfp609 or Nipbl from cortical neural progenitors in vivo is detrimental to neuronal migration. Zfp609 and Nipbl overlap at genomic binding sites independently of cohesin and regulate genes that control cortical neuron migration. We find that Zfp609 and Nipbl interact with the Integrator complex, which functions in RNA polymerase 2 pause release. Indeed, Zfp609 and Nipbl co-localize at gene promoters containing paused RNA polymerase 2, and Integrator similarly regulates neuronal migration. Our data provide a rationale and mechanistic insights for the role of Nipbl in the neurological defects associated with CdLS.


Assuntos
Movimento Celular/genética , Córtex Cerebral/crescimento & desenvolvimento , Síndrome de Cornélia de Lange/genética , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Neurais/citologia , Neurônios/citologia , Transativadores/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Camundongos , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Coesinas
10.
Science ; 353(6296): 292-5, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27418510

RESUMO

Quiescence is essential for long-term maintenance of adult stem cells. Niche signals regulate the transit of stem cells from dormant to activated states. Here, we show that the E3-ubiquitin ligase Huwe1 (HECT, UBA, and WWE domain-containing 1) is required for proliferating stem cells of the adult mouse hippocampus to return to quiescence. Huwe1 destabilizes proactivation protein Ascl1 (achaete-scute family bHLH transcription factor 1) in proliferating hippocampal stem cells, which prevents accumulation of cyclin Ds and promotes the return to a resting state. When stem cells fail to return to quiescence, the proliferative stem cell pool becomes depleted. Thus, long-term maintenance of hippocampal neurogenesis depends on the return of stem cells to a transient quiescent state through the rapid degradation of a key proactivation factor.


Assuntos
Células-Tronco Adultas/fisiologia , Hipocampo/embriologia , Células-Tronco Neurais/fisiologia , Neurogênese , Ubiquitina-Proteína Ligases/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células , Hipocampo/citologia , Camundongos , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Estabilidade Proteica , Proteólise , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases/genética
11.
Nat Commun ; 6: 7155, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25990348

RESUMO

The locations of transcriptional enhancers and promoters were recently mapped in many mammalian cell types. Proteins that bind those regulatory regions can determine cell identity but have not been systematically identified. Here we purify native enhancers, promoters or heterochromatin from embryonic stem cells by chromatin immunoprecipitations (ChIP) for characteristic histone modifications and identify associated proteins using mass spectrometry (MS). 239 factors are identified and predicted to bind enhancers or promoters with different levels of activity, or heterochromatin. Published genome-wide data indicate a high accuracy of location prediction by ChIP-MS. A quarter of the identified factors are important for pluripotency and includes Oct4, Esrrb, Klf5, Mycn and Dppa2, factors that drive reprogramming to pluripotent stem cells. We determined the genome-wide binding sites of Dppa2 and find that Dppa2 operates outside the classical pluripotency network. Our ChIP-MS method provides a detailed read-out of the transcriptional landscape representative of the investigated cell type.


Assuntos
Imunoprecipitação da Cromatina/métodos , Histonas/química , Animais , Sítios de Ligação , Domínio Catalítico , Células-Tronco Embrionárias/citologia , Elementos Facilitadores Genéticos , Genoma , Código das Histonas , Fatores de Transcrição Kruppel-Like/química , Espectrometria de Massas/métodos , Camundongos , Proteína Proto-Oncogênica N-Myc , Proteínas Nucleares/química , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Receptores de Estrogênio/química , Sequências Reguladoras de Ácido Nucleico , Reprodutibilidade dos Testes , Fatores de Transcrição
12.
Cell Rep ; 10(9): 1544-1556, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25753420

RESUMO

The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.

13.
Genome Res ; 25(1): 41-56, 2015 01.
Artigo em Inglês | MEDLINE | ID: mdl-25294244

RESUMO

The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Células Cultivadas , Análise por Conglomerados , Epigenômica , Modelos Logísticos , Camundongos , Análise em Microsséries , Modelos Teóricos , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismo , Análise de Sequência de DNA
14.
Cell Stem Cell ; 6(4): 369-381, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20362541

RESUMO

Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.


Assuntos
Células-Tronco Embrionárias/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes/genética , Espectrometria de Massas , Camundongos , Fenótipo , Ligação Proteica , Transporte Proteico , Fatores de Transcrição/química , Fatores de Transcrição/isolamento & purificação , Fatores de Transcrição/metabolismo
15.
Mol Cell Biol ; 28(19): 5986-95, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18662995

RESUMO

Embryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta (Esrrb). However, the mode of action of Esrrb in ES cells is unknown. Here, using an Oct4 affinity screen, we identify Esrrb as an Oct4 partner protein. Esrrb can interact with Oct4 independently of DNA. Esrrb is recruited near the Oct-Sox element in the Nanog proximal promoter, where it positively regulates Nanog expression. Esrrb recruitment to the Nanog promoter requires both the presence of Oct4 and a degenerate estrogen-related receptor DNA element. Consistent with its role in Nanog regulation, expression of the Esrrb protein within the Oct4-positive ES cell population is mosaic and correlates with the mosaic expression of the Nanog protein. Together with previous reports that Nanog may regulate Esrrb gene expression, our results suggest that Esrrb and Nanog act as part of a feedback regulatory circuit that modulates the fluctuating self-renewal capacity of ES cell populations.


Assuntos
Células-Tronco Embrionárias/metabolismo , Proteínas de Homeodomínio/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Linhagem Celular , Células-Tronco Embrionárias/citologia , Camundongos , Proteína Homeobox Nanog
16.
J Immunol ; 180(6): 3938-45, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18322202

RESUMO

Filamin A, or actin-binding protein 280, is a ubiquitously expressed cytosolic protein that interacts with intracellular domains of multiple receptors to control their subcellular distribution, and signaling capacity. In this study, we document interaction between FcgammaRI, a high-affinity IgG receptor, and filamin A by yeast two-hybrid techniques and coimmunoprecipitation. Both proteins colocalized at the plasma membrane in monocytes, but dissociated upon FcgammaRI triggering. The filamin-deficient cell line M2 and a filamin-reconstituted M2 subclone (A7), were used to further study FcgammaRI-filamin interactions. FcgammaRI transfection in A7 cells with filamin resulted in high plasma membrane expression levels. In filamin-deficient M2 cells and in filamin RNA-interference studies, FcgammaRI surface expression was consistently reduced. FcgammaRI localized to LAMP-1-positive vesicles in the absence of filamin as shown by confocal microscopy indicative for lysosomal localization. Mouse IgG2a capture experiments suggested a transient membrane expression of FcgammaRI before being transported to the lysosomes. These data support a pivotal role for filamin in FcgammaRI surface expression via retention of FcgammaRI from a default lysosomal pathway.


Assuntos
Proteínas Contráteis/fisiologia , Lisossomos/metabolismo , Proteínas dos Microfilamentos/fisiologia , Receptores de IgG/biossíntese , Receptores de IgG/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/genética , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Células Clonais , Proteínas Contráteis/deficiência , Proteínas Contráteis/genética , Proteínas Contráteis/metabolismo , Filaminas , Humanos , Lisossomos/genética , Lisossomos/imunologia , Camundongos , Proteínas dos Microfilamentos/deficiência , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transporte Proteico/genética , Transporte Proteico/imunologia , Receptores de IgG/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Frações Subcelulares/imunologia , Frações Subcelulares/metabolismo , Células U937
17.
Cell Cycle ; 4(4): 543-6, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15753658

RESUMO

During DNA replication, chromatin states have to be accurately transmitted from the parental to the daughter strands for faithful epigenetic inheritance. Chromatin remodelling factors at the replication site are thought to be involved in this process. Recent work adds ATP-dependent nucleosome remodelling factors to this category of enzymes. The WICH complex, consisting of the ISWI-type ATPase SNF2H and the Williams Syndrome Transcription Factor (WSTF), binds to replication foci using PCNA, a key factor in DNA- and chromatin replication and DNA repair, as an interaction platform. Depletion of WSTF results in decreased chromatin accessibility, which is evident already in newly replicated DNA. This leads to heterochromatin formation on a global scale and a decrease in overall transcriptional activity. Here, we propose that WICH, by keeping nucleosomes mobile, provides access to the newly replicated DNA and may thereby create a window of opportunity after DNA replication for rebinding of factors that maintain the epigenetic state, and thus prevents aberrant heterochromatin formation. Our model may provide an explanation for the long-standing observation of a delay in chromatin "maturation" on newly replicated DNA, by connecting this delay with the action of PCNA-bound WSTF-ISWI, and highlights chromatin remodeling shortly after DNA replication as a critical point for regulation.


Assuntos
Adenosina Trifosfatases/fisiologia , Cromatina/química , Regulação da Expressão Gênica , Fatores de Transcrição/fisiologia , Animais , Sítios de Ligação , Ciclo Celular , DNA/química , Replicação do DNA , Epigênese Genética , Heterocromatina/química , Humanos , Modelos Biológicos , Nucleossomos/química , Ligação Proteica
18.
Nat Cell Biol ; 6(12): 1236-44, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15543136

RESUMO

Chromatin states have to be faithfully duplicated during DNA replication to maintain cell identity. It is unclear whether or how ATP-dependent chromatin-remodelling factors are involved in this process. Here we provide evidence that the Williams syndrome transcription factor (WSTF) is targeted to replication foci through direct interaction with the DNA clamp PCNA, an important coordinator of DNA and chromatin replication. WSTF, in turn, recruits imitation switch (ISWI)-type nucleosome-remodelling factor SNF2H to replication sites. These findings reveal a novel recruitment mechanism for ATP-dependent chromatin-remodelling factors that is fundamentally different from the previously documented targeting by sequence-specific transcriptional regulators. RNA-interference-mediated depletion of WSTF or SNF2H causes a compaction of newly replicated chromatin and increases the amount of heterochromatin markers, including HP1beta. This increase in the amount of HP1beta protein is mediated by progression through S phase and is not the result of an increase in HP1beta mRNA levels. We propose that the WSTF-ISWI complex has a role in the maintenance of chromatin structures during DNA replication.


Assuntos
Adenosina Trifosfatases/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , Replicação do DNA/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fatores de Transcrição/metabolismo , Síndrome de Williams/genética , Adenosina Trifosfatases/genética , Trifosfato de Adenosina/metabolismo , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/genética , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos Humanos Par 7/genética , Marcadores Genéticos/genética , Células HeLa , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Interferência de RNA , Fatores de Transcrição/genética , Síndrome de Williams/metabolismo
19.
J Biol Chem ; 279(12): 10848-54, 2004 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-14707134

RESUMO

The evolutionary conserved Ccr4-Not complex controls mRNA metabolism at multiple levels in eukaryotic cells. Genetic analysis of not mutants in yeast identifies a negative role in transcription, which is dependent on core promoter structure. To obtain direct support for this we targeted individual core subunits of the human Ccr4-Not complex to promoters in transient transfections of human cells. In this experimental setup we found that the CNOT2 and CNOT9(hRcd1/hCaf40) subunits act as repressors of reporter gene activity. Interestingly, recruitment of other Ccr4-Not subunits did not affect the reporter gene. The major repression function of CNOT2 is localized in a specialized protein motif, the Not-Box. This conserved motif is present in all CNOT2 orthologs and surprisingly also in CNOT3 orthologs. Repression by the Not-Box was sensitive to treatment with the histone deacetylase inhibitor trichostatin A. In addition, mutation of a canonical TATA-box enhanced repression. Our experiments show for the first time direct regulation of promoter activity by components of the Ccr4-Not complex.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica/fisiologia , Regiões Promotoras Genéticas , Proteínas Repressoras/fisiologia , Fatores de Transcrição/fisiologia , Sequência de Aminoácidos , Linhagem Celular , Proteínas de Ligação a DNA/química , Genes Reporter , Humanos , Dados de Sequência Molecular , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Proteínas Repressoras/química , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/química
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