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2.
Nat Commun ; 12(1): 5056, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417458

RESUMO

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.


Assuntos
Epigênese Genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Micrometástase de Neoplasia , Ligação Proteica , Carga Tumoral
3.
Cell Stem Cell ; 24(4): 637-653.e9, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951662

RESUMO

Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program.


Assuntos
Melanoma/metabolismo , Melanoma/patologia , Crista Neural/citologia , Crista Neural/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Fator de Transcrição YY1/deficiência
4.
Cell Stem Cell ; 21(5): 679-693.e6, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29033351

RESUMO

To identify the cells at the origin of melanoma, we combined single-cell lineage-tracing and transcriptomics approaches with time-lapse imaging. A mouse model that recapitulates key histopathological features of human melanomagenesis was created by inducing a BRafV600E-driven melanomagenic program in tail interfollicular melanocytes. Most targeted mature, melanin-producing melanocytes expanded clonally within the epidermis before losing their differentiated features through transcriptional reprogramming and eventually invading the dermis. Tumors did not form within interscales, which contain both mature and dormant amelanotic melanocytes. The hair follicle bulge, which contains melanocyte stem cells, was also refractory to melanomagenesis. These studies identify varying tumor susceptibilities within the melanocytic lineage, highlighting pigment-producing cells as the melanoma cell of origin, and indicate that regional variation in tumor predisposition is dictated by microenvironmental cues rather than intrinsic differences in cellular origin. Critically, this work provides in vivo evidence that differentiated somatic cells can be reprogrammed into cancer initiating cells.


Assuntos
Desdiferenciação Celular , Melanócitos/patologia , Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Pigmentação da Pele , Animais , Biomarcadores/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Proliferação de Células , Derme/patologia , Folículo Piloso/patologia , Humanos , Melanócitos/metabolismo , Melanoma/patologia , Camundongos , Invasividade Neoplásica , Neoplasias Cutâneas/patologia , Nicho de Células-Tronco , Cauda , Transcriptoma/genética
5.
J Neuroinflammation ; 12: 62, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25889302

RESUMO

BACKGROUND: Oligodendrocytes are myelinating cells of the central nervous system which support functionally, structurally, and metabolically neurons. Mature oligodendrocytes are generally believed to be mere targets of destruction in the context of neuroinflammation and tissue damage, but their real degree of in vivo plasticity has become a matter of debate. We thus investigated the in vivo dynamic, actin-related response of these cells under different kinds of demyelinating stress. METHODS: We used a novel mouse model (oLucR) expressing luciferase in myelin oligodendrocyte glycoprotein-positive oligodendrocytes under the control of a ß-actin promoter. Activity of this promoter served as surrogate for dynamics of the cytoskeleton gene transcription through recording of in vivo bioluminescence following diphtheria toxin-induced oligodendrocyte death and autoimmune demyelination. Cytoskeletal gene expression was quantified from mature oligodendrocytes directly isolated from transgenic animals through cell sorting. RESULTS: Experimental demyelinating setups augmented oligodendrocyte-specific in vivo bioluminescence. These changes in luciferase signal were confirmed by further ex vivo analysis of the central nervous system tissue from oLucR mice. Increase in bioluminescence upon autoimmune inflammation was parallel to an oligodendrocyte-specific increased transcription of ß-tubulin. CONCLUSIONS: Mature oligodendrocytes acutely increase their cytoskeletal plasticity in vivo during demyelination. They are therefore not passive players under demyelinating conditions but can rather react dynamically to external insults.


Assuntos
Doenças do Sistema Nervoso Central/patologia , Sistema Nervoso Central/metabolismo , Citoesqueleto/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Oligodendroglia/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Citocinas/metabolismo , Toxina Diftérica/farmacologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Glicoproteína Mielina-Oligodendrócito/genética
6.
Cell Stem Cell ; 16(3): 314-22, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25748934

RESUMO

The neural crest (NC) is an embryonic stem/progenitor cell population that generates a diverse array of cell lineages, including peripheral neurons, myelinating Schwann cells, and melanocytes, among others. However, there is a long-standing controversy as to whether this broad developmental perspective reflects in vivo multipotency of individual NC cells or whether the NC is comprised of a heterogeneous mixture of lineage-restricted progenitors. Here, we resolve this controversy by performing in vivo fate mapping of single trunk NC cells both at premigratory and migratory stages using the R26R-Confetti mouse model. By combining quantitative clonal analyses with definitive markers of differentiation, we demonstrate that the vast majority of individual NC cells are multipotent, with only few clones contributing to single derivatives. Intriguingly, multipotency is maintained in migratory NC cells. Thus, our findings provide definitive evidence for the in vivo multipotency of both premigratory and migrating NC cells in the mouse.


Assuntos
Antígenos de Diferenciação/metabolismo , Linhagem da Célula/fisiologia , Movimento Celular/fisiologia , Células-Tronco Multipotentes/metabolismo , Crista Neural/embriologia , Crista Neural/metabolismo , Animais , Camundongos , Camundongos Transgênicos , Células-Tronco Multipotentes/citologia , Crista Neural/citologia
7.
J Neurosci ; 34(17): 6112-22, 2014 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-24760871

RESUMO

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.


Assuntos
Diferenciação Celular/fisiologia , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Crista Neural/metabolismo , Células-Tronco Neurais/metabolismo , Oligodendroglia/metabolismo , Células de Schwann/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Camundongos , Crista Neural/citologia , Células-Tronco Neurais/citologia , Oligodendroglia/citologia , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/citologia
8.
Development ; 141(4): 867-77, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24496623

RESUMO

The emergence of craniofacial skeletal elements, and of the jaw in particular, was a crucial step in the evolution of higher vertebrates. Most facial bones and cartilage are generated during embryonic development by cranial neural crest cells, while an osteochondrogenic fate is suppressed in more posterior neural crest cells. Key players in this process are Hox genes, which suppress osteochondrogenesis in posterior neural crest derivatives. How this specific pattern of osteochondrogenic competence is achieved remains to be elucidated. Here we demonstrate that Hox gene expression and osteochondrogenesis are controlled by epigenetic mechanisms. Ezh2, which is a component of polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 in histone 3 (H3K27me3), thereby functioning as transcriptional repressor of target genes. Conditional inactivation of Ezh2 does not interfere with localization of neural crest cells to their target structures, neural development, cell cycle progression or cell survival. However, loss of Ezh2 results in massive derepression of Hox genes in neural crest cells that are usually devoid of Hox gene expression. Accordingly, craniofacial bone and cartilage formation is fully prevented in Ezh2 conditional knockout mice. Our data indicate that craniofacial skeleton formation in higher vertebrates is crucially dependent on epigenetic regulation that keeps in check inhibitors of an osteochondrogenic differentiation program.


Assuntos
Cartilagem/embriologia , Condrogênese/fisiologia , Epigênese Genética/fisiologia , Ossos Faciais/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Crista Neural/fisiologia , Osteogênese/fisiologia , Complexo Repressor Polycomb 2/metabolismo , Azul Alciano , Animais , Antraquinonas , Imunoprecipitação da Cromatina , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Citometria de Fluxo , Galactosídeos , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/metabolismo , Imuno-Histoquímica , Indóis , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Crista Neural/metabolismo , Complexo Repressor Polycomb 2/genética , Reação em Cadeia da Polimerase em Tempo Real
9.
Nat Neurosci ; 14(4): 429-36, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21423190

RESUMO

Histone deacetylases (HDACs) are major epigenetic regulators. We show that HDAC1 and HDAC2 functions are critical for myelination of the peripheral nervous system. Using mouse genetics, we have ablated Hdac1 and Hdac2 specifically in Schwann cells, resulting in massive Schwann cell loss and virtual absence of myelin in mutant sciatic nerves. Expression of Sox10 and Krox20, the main transcriptional regulators of Schwann cell myelination, was greatly reduced. We demonstrate that in Schwann cells, HDAC1 and HDAC2 exert specific primary functions: HDAC2 activates the transcriptional program of myelination in synergy with Sox10, whereas HDAC1 controls Schwann cell survival by regulating the levels of active ß-catenin.


Assuntos
Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Fibras Nervosas Mielinizadas/enzimologia , Células de Schwann/enzimologia , Nervo Isquiático/enzimologia , Nervo Isquiático/crescimento & desenvolvimento , Ativação Transcricional/genética , Animais , Animais Recém-Nascidos , Comunicação Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Histona Desacetilase 1/fisiologia , Histona Desacetilase 2/fisiologia , Camundongos , Camundongos Knockout , Mutação , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Ratos , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição SOXE/fisiologia , Células de Schwann/patologia , Células de Schwann/ultraestrutura , Nervo Isquiático/patologia , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/fisiologia
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