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1.
Nature ; 610(7932): 569-574, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36198799

RESUMO

Deoxyribonucleic acid in eukaryotes wraps around the histone octamer to form nucleosomes1, the fundamental unit of chromatin. The N termini of histone H4 interact with nearby nucleosomes and play an important role in the formation of high-order chromatin structure and heterochromatin silencing2-4. NuA4 in yeast and its homologue Tip60 complex in mammalian cells are the key enzymes that catalyse H4 acetylation, which in turn regulates chromatin packaging and function in transcription activation and DNA repair5-10. Here we report the cryo-electron microscopy structure of NuA4 from Saccharomyces cerevisiae bound to the nucleosome. NuA4 comprises two major modules: the catalytic histone acetyltransferase (HAT) module and the transcription activator-binding (TRA) module. The nucleosome is mainly bound by the HAT module and is positioned close to a polybasic surface of the TRA module, which is important for the optimal activity of NuA4. The nucleosomal linker DNA carrying the upstream activation sequence is oriented towards the conserved, transcription activator-binding surface of the Tra1 subunit, which suggests a potential mechanism of NuA4 to act as a transcription co-activator. The HAT module recognizes the disk face of the nucleosome through the H2A-H2B acidic patch and nucleosomal DNA, projecting the catalytic pocket of Esa1 to the N-terminal tail of H4 and supporting its function in selective acetylation of H4. Together, our findings illustrate how NuA4 is assembled and provide mechanistic insights into nucleosome recognition and transcription co-activation by a HAT.


Assuntos
Microscopia Crioeletrônica , Histona Acetiltransferases , Nucleossomos , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Animais , Acetilação , DNA/química , DNA/metabolismo , DNA/ultraestrutura , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Histona Acetiltransferases/ultraestrutura , Histonas/química , Histonas/metabolismo , Histonas/ultraestrutura , Nucleossomos/química , Nucleossomos/metabolismo , Nucleossomos/ultraestrutura , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/ultraestrutura , Fatores de Transcrição/metabolismo
2.
Cell Rep ; 15(7): 1467-1480, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27160914

RESUMO

The growth plate (GP) comprising sequentially differentiated cell layers is a critical structure for bone elongation and regeneration. Although several key regulators in GP development have been identified using genetic perturbation, systematic understanding is still limited. Here, we used single-cell RNA-sequencing (RNA-seq) to determine the gene expression profiles of 217 single cells from GPs and developed a bioinformatics pipeline named Sinova to de novo reconstruct physiological GP development in both temporal and spatial high resolution. Our unsupervised model not only confirmed prior knowledge, but also enabled the systematic discovery of genes, potential signal pathways, and surface markers CD9/CD200 to precisely depict development. Sinova further identified the effective combination of transcriptional factors (TFs) that regulates GP maturation, and the result was validated using an in vitro EGFP-Col10a screening system. Our case systematically reconstructed molecular cascades in GP development through single-cell profiling, and the bioinformatics pipeline is applicable to other developmental processes. VIDEO ABSTRACT.


Assuntos
Lâmina de Crescimento/embriologia , Lâmina de Crescimento/metabolismo , Análise de Sequência de RNA/métodos , Transdução de Sinais/genética , Análise de Célula Única/métodos , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Padronização Corporal/genética , Citometria de Fluxo , Redes Reguladoras de Genes , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Fatores de Tempo , Fatores de Transcrição/metabolismo
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