GCN5 acetylation is required for craniofacial chondrocyte maturation

Sofia A. Pezoa, Kristin B. Artinger, Lee A. Niswander

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Development of the craniofacial structures requires the precise differentiation of cranial neural crest cells into osteoblasts or chondrocytes. Here, we explore the epigenetic and non-epigenetic mechanisms that are required for the development of craniofacial chondrocytes. We previously demonstrated that the acetyltransferase activity of the highly conserved acetyltransferase GCN5, or KAT2A, is required for murine craniofacial development. We show that Gcn5 is required cell autonomously in the cranial neural crest. Moreover, GCN5 is required for chondrocyte development following the arrival of the cranial neural crest within the pharyngeal arches. Using a combination of in vivo and in vitro inhibition of GCN5 acetyltransferase activity, we demonstrate that GCN5 is a potent activator of chondrocyte maturation, acting to control chondrocyte maturation and size increase during pre-hypertrophic maturation to hypertrophic chondrocytes. Rather than acting as an epigenetic regulator of histone H3K9 acetylation, our findings suggest GCN5 primarily acts as a non-histone acetyltransferase to regulate chondrocyte development. Here, we investigate the contribution of GCN5 acetylation to the activity of the mTORC1 pathway. Our findings indicate that GCN5 acetylation is required for activation of this pathway, either via direct activation of mTORC1 or through indirect mechanisms. We also investigate one possibility of how mTORC1 activity is regulated through RAPTOR acetylation, which is hypothesized to enhance mTORC1 downstream phosphorylation. This study contributes to our understanding of the specificity of acetyltransferases, and the cell type specific roles in which these enzymes function.

Original languageEnglish (US)
Pages (from-to)24-34
Number of pages11
JournalDevelopmental Biology
Volume464
Issue number1
DOIs
StatePublished - Aug 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work is supported by NIH NIDCR R01 DE024034 to K.B.A. and L.A.N., and R01 DE024034-A1S1 to S.A.P.

Funding Information:
We would like to acknowledge members of the Niswander and Artinger labs for their help and feedback during the course of these experiments. We would also like to thank Lori Bulwith and the CU Boulder Office for Animal Resources staff for their support and help with mouse husbandry. Lastly, we would like to thank the CU Boulder Light Microscopy Core and Stem Cell Research and Technology Resource Center for their help with imaging.This work is supported by NIH NIDCR R01 DE024034 to K.B.A. and L.A.N., and R01 DE024034-A1S1 to S.A.P.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Acetyltransferase
  • Chondrocyte
  • Craniofacial development
  • GCN5
  • Kat2a
  • Neural crest

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