RESUMO
Lineage tracing of specific populations of progenitor cells provides crucial information about developmental programs. Four members of the Dlx homeobox gene family, Dlx1,2, 5 and 6, are involved in the specification of γ-aminobutyric acid (GABA)ergic neurons in the vertebrate forebrain. Orthologous genes in mammals and teleost show similarities in expression patterns and transcriptional regulation mechanisms. We have used lineage tracing to permanently label dlx-expressing cells in the zebrafish and have characterized the progeny of these cells in the larva and in the juvenile and adult brain. We have found that dlx1a/2a and dlx5a/6a expressing progenitors give rise, for the most part, to small populations of cells which constitute only a small proportion of GABAergic cells in the adult brain tissue. Moreover, some of the cells do not acquire a neuronal phenotype suggesting that, regardless of the time a cell expresses dlx genes in the brain, it can potentially give rise to cells other than neurons. In some instances, labeling larval dlx5a/6a-expressing cells, but not dlx1a/2a-expressing cells, results in massively expanding, widespread clonal expansion throughout the adult brain. Our data provide a detailed lineage analysis of the dlx1a/2a and dlx5a/6a expressing progenitors in the zebrafish brain and lays the foundation for further characterization of the role of these transcription factors beyond the specification of GABAergic neurons.
Assuntos
Encéfalo/metabolismo , Neurônios GABAérgicos/metabolismo , Proteínas de Homeodomínio/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Encéfalo/citologia , Encéfalo/embriologia , Linhagem da Célula/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Neurônios GABAérgicos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Hibridização In Situ , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Células-Tronco Embrionárias Murinas/citologia , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Proteína Vermelha FluorescenteRESUMO
The appropriate coordination between epigenetic regulators is essential for spatial and temporal regulation of gene expression and maintenance of cell identity. Cancer is a disease driven by both genetic and epigenetic alterations. The widespread dysregulation and reversible nature of epigenetic alterations confer cancer cells with vulnerabilities for therapeutic interventions. Over the past decades, remarkable progress has been made in developing drugs that target epigenetic regulators, with many drugs under evaluation in clinical trials. Here, we summarize the epigenetic drugs currently in clinical investigations and highlight the potentials and challenges in their implication to treat cancer. We also discuss the preclinical and clinical results of combination therapies with epigenetic drugs and other therapies such as targeted and immune-based therapies.
Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA , Epigênese Genética , Histonas/genética , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Cromatina/química , Cromatina/efeitos dos fármacos , Cromatina/imunologia , Terapia Combinada/métodos , Drogas em Investigação/uso terapêutico , Histonas/antagonistas & inibidores , Histonas/imunologia , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Transcrição Gênica , Resultado do TratamentoRESUMO
Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/diagnóstico , Metilação de DNA/genética , Epigenoma/genética , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ácidos Nucleicos Livres/sangue , Ilhas de CpG/genética , DNA de Neoplasias/sangue , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MasculinoRESUMO
We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.