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Identification of drought stress related genes in NatA depleted mutants

ABSTRACT: N-terminal protein acetylation is one of the most common protein modifications in eucaryotes and is catalyzed co-translationally by N-terminal aceytltransferases (Nats). Regarding the number of predictaed substrates, NatA is the main Nat complex in human and yeast and is composed of the catalytic subunit NAA10 and the auxilliary subunit NAA15. The down-regulation of NAA10 and NAA15 results in Arabidopsis in drought resistant plants. This study focus on the identification of altered gene expression leading to the drought resistant phenotype. Microarray analysis was used to identify misregulated genes in the NatA depleted mutants responsible for the drought resistant phenotype

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE65414 | GEO | 2015/07/23

SECONDARY ACCESSION(S): PRJNA273928

REPOSITORIES: GEO

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Project description:Rationale- NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective- We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15.Methods and Results - We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions - These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

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Identification of drought stress related genes in NatA depleted mutants

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