GCN5 acetylation is required for craniofacial chondrocyte maturation.

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.

journal_name

Dev Biol

journal_title

Developmental biology

authors

Pezoa SA,Artinger KB,Niswander LA

doi

10.1016/j.ydbio.2020.05.006

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

24-34

issue

1

eissn

0012-1606

issn

1095-564X

pii

S0012-1606(20)30151-2

journal_volume

464

pub_type

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