PgmNr M262: Post-translational mechanisms buffer protein abundance against transcriptional variation.

Authors:
G. A. Churchill 1 ; S. C. Munger 1 ; J. M. Chick 2 ; S. P. Gygi 2


Institutes
1) Jackson Lab, Bar Harbor, ME; 2) Harvard Medical School, Cambridge, MA.


Abstract:

Recent studies have reported low correlation among transcript and protein levels in mouse tissues and human lymphoblastoid cell populations. Here we describe the largest combined RNA-seq and shotgun proteomics study to date, in liver samples from genetically heterogeneous Diversity Outbred (DO) mice. We observe two classes of gene regulation that act on protein levels. Most protein abundance QTL (pQTL) map locally to the gene region and act in cis to affect both message and protein, resulting in high concordance between transcript and protein levels. In stark contrast, proteins with distant pQTL appear largely uncoupled from transcript abundance. We apply a novel conditioning approach to identify causal regulatory proteins and transcripts underlying distant pQTL. We discover that stoichiometric buffering of protein complexes and metabolic pathways is the predominant trans-acting post-translational mechanism that buffers protein levels against cis genetic variation in the protein-coding gene.