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1.
Dev Biol ; 504: 128-136, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37805104

RESUMO

Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated in Smarcc1 conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.


Assuntos
Cromatina , Botões de Extremidades , Animais , Camundongos , Cromatina/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Botões de Extremidades/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo
2.
Bioessays ; 44(12): e2200139, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36251875

RESUMO

Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been presumed that GLI proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre-patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time. These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre-patterning, digit regulation, and HH-driven disease.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Fatores de Transcrição/metabolismo , Transdução de Sinais/fisiologia , Expressão Gênica
3.
J Biol Chem ; 291(13): 7171-82, 2016 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-26797124

RESUMO

The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We found that both GLI3 and GLI1 bind to the pluripotency factor NANOG. The ectopic expression of NANOG inhibits GLI1-mediated transcriptional responses in a dose-dependent fashion. In differentiating ES cells, the presence of NANOG reduces the transcriptional response of cells to HH. Finally, we found thatGli1andNanogare co-expressed in ES cells at high levels. We propose that NANOG acts as a negative feedback component that provides stem cell-specific regulation of the HH pathway.


Assuntos
Proteínas Hedgehog/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição Kruppel-Like/genética , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas do Tecido Nervoso/genética , Animais , Diferenciação Celular , Retroalimentação Fisiológica , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células NIH 3T3 , Proteína Homeobox Nanog , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Transdução de Sinais , Transcrição Gênica , Proteína GLI1 em Dedos de Zinco , Proteína Gli3 com Dedos de Zinco
4.
bioRxiv ; 2023 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-36798239

RESUMO

Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated in Smarcc1 conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.

5.
Nat Commun ; 13(1): 808, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145123

RESUMO

The Hedgehog (HH) pathway regulates a spectrum of developmental processes through the transcriptional mediation of GLI proteins. GLI repressors control tissue patterning by preventing sub-threshold activation of HH target genes, presumably even before HH induction, while lack of GLI repression activates most targets. Despite GLI repression being central to HH regulation, it is unknown when it first becomes established in HH-responsive tissues. Here, we investigate whether GLI3 prevents precocious gene expression during limb development. Contrary to current dogma, we find that GLI3 is inert prior to HH signaling. While GLI3 binds to most targets, loss of Gli3 does not increase target gene expression, enhancer acetylation or accessibility, as it does post-HH signaling. Furthermore, GLI repression is established independently of HH signaling, but after its onset. Collectively, these surprising results challenge current GLI pre-patterning models and demonstrate that GLI repression is not a default state for the HH pathway.


Assuntos
Proteínas Hedgehog/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Transdução de Sinais , Fatores de Transcrição/metabolismo , Transcriptoma
6.
Elife ; 92020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31989924

RESUMO

Transcriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of GLI binding regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific transcriptional activity in the mouse limb bud. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. Furthermore, the Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target genes by altering the acetylation status at enhancers.


Assuntos
Desenvolvimento Embrionário/fisiologia , Proteínas Hedgehog/metabolismo , Botões de Extremidades/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transativadores/metabolismo , Animais , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Histonas/metabolismo , Camundongos , Camundongos Knockout , Células NIH 3T3 , Proteínas do Tecido Nervoso/genética , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo
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