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1.
Nat Cell Biol ; 25(12): 1873-1883, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37996647

RESUMO

Gene expression is regulated by multiple epigenetic mechanisms, which are coordinated in development and disease. However, current multiomics methods are frequently limited to one or two modalities at a time, making it challenging to obtain a comprehensive gene regulatory signature. Here, we describe a method-3D genome, RNA, accessibility and methylation sequencing (3DRAM-seq)-that simultaneously interrogates spatial genome organization, chromatin accessibility and DNA methylation genome-wide and at high resolution. We combine 3DRAM-seq with immunoFACS and RNA sequencing in cortical organoids to map the cell-type-specific regulatory landscape of human neural development across multiple epigenetic layers. Finally, we apply a massively parallel reporter assay to profile cell-type-specific enhancer activity in organoids and to functionally assess the role of key transcription factors for human enhancer activation and function. More broadly, 3DRAM-seq can be used to profile the multimodal epigenetic landscape in rare cell types and different tissues.


Assuntos
Cromatina , Epigenoma , Humanos , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Metilação de DNA/genética , Organoides/metabolismo
2.
Nat Neurosci ; 25(2): 154-167, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35132236

RESUMO

How multiple epigenetic layers and transcription factors (TFs) interact to facilitate brain development is largely unknown. Here, to systematically map the regulatory landscape of neural differentiation in the mouse neocortex, we profiled gene expression and chromatin accessibility in single cells and integrated these data with measurements of enhancer activity, DNA methylation and three-dimensional genome architecture in purified cell populations. This allowed us to identify thousands of new enhancers, their predicted target genes and the temporal relationships between enhancer activation, epigenome remodeling and gene expression. We characterize specific neuronal transcription factors associated with extensive and frequently coordinated changes across multiple epigenetic modalities. In addition, we functionally demonstrate a new role for Neurog2 in directly mediating enhancer activity, DNA demethylation, increasing chromatin accessibility and facilitating chromatin looping in vivo. Our work provides a global view of the gene regulatory logic of lineage specification in the cerebral cortex.


Assuntos
Cromatina , Epigenoma , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Metilação de DNA/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Cell Rep ; 27(3): 719-729.e6, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995471

RESUMO

Long non-coding RNAs (lncRNAs) show patterns of tissue- and cell type-specific expression that are very similar to those of protein coding genes and consequently have the potential to control stem and progenitor cell fate decisions along a differentiation trajectory. To understand the roles that lncRNAs may play in hematopoiesis, we selected a subset of mouse lncRNAs with potentially relevant expression patterns and refined our candidate list using evidence of conserved expression in human blood lineages. For each candidate, we assessed its possible role in hematopoietic differentiation in vivo using competitive transplantation. Our studies identified two lncRNAs that were required for hematopoiesis. One of these, Spehd, showed defective multilineage differentiation, and its silencing yielded common myeloid progenitors that are deficient in their oxidative phosphorylation pathway. This effort not only suggests that lncRNAs can contribute to differentiation decisions during hematopoiesis but also provides a path toward the identification of functional lncRNAs in other differentiation hierarchies.


Assuntos
Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Transplante de Medula Óssea , Linhagem Celular Tumoral , Linhagem da Célula , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/citologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação Oxidativa , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Regeneração , Transativadores/antagonistas & inibidores , Transativadores/genética , Transativadores/metabolismo
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