Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.

Systematic proteome and proteostasis profiling in human trisomy 21 fibroblast cells / Y. Liu, C. Borel, L. Li, T. Müller, E.G. Williams, P. Germain, M. Buljan, T. Sajic, P.J. Boersema, W. Shao, M. Faini, G. Testa, A. Beyer, S.E. Antonarakis, R. Aebersold. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8(2017), pp. 1212.1-1212.15.

Systematic proteome and proteostasis profiling in human trisomy 21 fibroblast cells

P. Germain;G. Testa;
2017

Abstract

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.
chemistry (all); biochemistry, genetics and molecular biology (all); physics and astronomy (all)
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore MED/04 - Patologia Generale
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/542252
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