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Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy.

Coni S, Antonucci L, D'Amico D, Di Magno L, Infante P, De Smaele E, Giannini G, Di Marcotullio L, Screpanti I, Gulino A, Canettieri G - PLoS ONE (2013)

Bottom Line: Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling.Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin.Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7277, Inserm 1091, Institut de Biologie Valrose (iBV), Centre de Biochimie, Nice, France.

ABSTRACT
The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p300, but not other HATs, acetylates Gli2 at the conserved lysine K757 thus inhibiting Hh target gene expression. By generating a specific anti acetyl-Gli2(Lys757) antisera we demonstrated that Gli2 acetylation is readily detectable at endogenous levels and is attenuated by Hh agonists. Moreover, Gli2 K757R mutant activity is higher than wild type Gli2 and is no longer enhanced by Hh agonists, indicating that acetylation represents an additional level of control for signal dependent activation. Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling. Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin. Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

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Acetylation of Gli transcription factors is not detectable in the External Granular Layer.Immunohistochemical staining of Gli1(upper-right), acetyl-Gli1(Lys518) (bottom-left), acetyl-GLi2(Lys757) (bottom-right), or Hematoxylin (upper-left) in a 6-day-old mouse cerebellum.
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pone-0065718-g003: Acetylation of Gli transcription factors is not detectable in the External Granular Layer.Immunohistochemical staining of Gli1(upper-right), acetyl-Gli1(Lys518) (bottom-left), acetyl-GLi2(Lys757) (bottom-right), or Hematoxylin (upper-left) in a 6-day-old mouse cerebellum.

Mentions: Confirming the increased Hh activation status, incubation of sections with anti Gli1 antisera, strongly stained the EGL (Fig. 3). In contrast, neither acetylated Gli1 nor acetylated Gli2 were detectable in the same region, thus indicating that both these Hh transcriptional activators are deacetylated in the EGL at this stage of development.


Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy.

Coni S, Antonucci L, D'Amico D, Di Magno L, Infante P, De Smaele E, Giannini G, Di Marcotullio L, Screpanti I, Gulino A, Canettieri G - PLoS ONE (2013)

Acetylation of Gli transcription factors is not detectable in the External Granular Layer.Immunohistochemical staining of Gli1(upper-right), acetyl-Gli1(Lys518) (bottom-left), acetyl-GLi2(Lys757) (bottom-right), or Hematoxylin (upper-left) in a 6-day-old mouse cerebellum.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675076&req=5

pone-0065718-g003: Acetylation of Gli transcription factors is not detectable in the External Granular Layer.Immunohistochemical staining of Gli1(upper-right), acetyl-Gli1(Lys518) (bottom-left), acetyl-GLi2(Lys757) (bottom-right), or Hematoxylin (upper-left) in a 6-day-old mouse cerebellum.
Mentions: Confirming the increased Hh activation status, incubation of sections with anti Gli1 antisera, strongly stained the EGL (Fig. 3). In contrast, neither acetylated Gli1 nor acetylated Gli2 were detectable in the same region, thus indicating that both these Hh transcriptional activators are deacetylated in the EGL at this stage of development.

Bottom Line: Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling.Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin.Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7277, Inserm 1091, Institut de Biologie Valrose (iBV), Centre de Biochimie, Nice, France.

ABSTRACT
The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p300, but not other HATs, acetylates Gli2 at the conserved lysine K757 thus inhibiting Hh target gene expression. By generating a specific anti acetyl-Gli2(Lys757) antisera we demonstrated that Gli2 acetylation is readily detectable at endogenous levels and is attenuated by Hh agonists. Moreover, Gli2 K757R mutant activity is higher than wild type Gli2 and is no longer enhanced by Hh agonists, indicating that acetylation represents an additional level of control for signal dependent activation. Consistently, in sections of developing mouse cerebella Gli2 acetylation correlates with the activation status of Hedgehog signaling. Mechanistically, acetylation at K757 prevents Gli2 entry into chromatin. Together, these data illustrate a novel mechanism of regulation of the Hh signaling whereby, in concert with Gli1, Gli2 acetylation functions as a key transcriptional checkpoint in the control of morphogen-dependent processes.

Show MeSH
Related in: MedlinePlus