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mRNAs, proteins and the emerging principles of gene expression control

Abstract

Gene expression involves transcription, translation and the turnover of mRNAs and proteins. The degree to which protein abundances scale with mRNA levels and the implications in cases where this dependency breaks down remain an intensely debated topic. Here we review recent mRNA–protein correlation studies in the light of the quantitative parameters of the gene expression pathway, contextual confounders and buffering mechanisms. Although protein and mRNA levels typically show reasonable correlation, we describe how transcriptomics and proteomics provide useful non-redundant readouts. Integrating both types of data can reveal exciting biology and is an essential step in refining our understanding of the principles of gene expression control.

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Fig. 1: Overview of the gene expression pathway.
Fig. 2: Across-gene and within-gene correlations between mRNA and protein levels.
Fig. 3: Quantitative parameters of the gene expression pathway.
Fig. 4: Predicting protein levels from mRNA levels.
Fig. 5: Contextual confounders of mRNA–protein correlations.
Fig. 6: Mechanisms of buffering between mRNA and protein levels.

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Acknowledgements

The authors acknowledge the extensive contributions of the scientific community to the topic of this Review and apologize for being unable to reference all pertinent articles. The authors thank P. Mertins, J. Wolf, D. Harnett (all from the Max Delbrück Center for Molecular Medicine) and E. McShane (Harvard Medical School) for feedback. They also thank T. Melder (Max Delbrück Center for Molecular Medicine) for help with the chemical structures and all other members of the Selbach laboratory for helpful discussions.

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Glossary

Genotype

The complement of DNA possessed by an organism.

Phenotype

The observable characteristics of an organism, which results from the genotype and its interaction with the environment.

Non-coding RNAs

RNAs transcribed from the genome that do not serve as templates for proteins (for example, microRNAs).

Ubiquitin–proteasome system

An ancient system conserved across species that is responsible for the regulated catabolism of individual proteins. Classes of enzymes (E1, E2 and E3) function in specifically ubiquitylating proteins within the cell, thus targeting these clients for destruction by the proteasome.

Autophagy

A form of cellular catabolism that is responsible for the removal of large cellular components (for instance, protein aggregates or damaged organelles). Autophagy involves the inclusion of these components within double-membraned vesicles (termed ‘autophagosomes’), which then undergo fusion with lysosomes.

Omics technologies

A generic term referring to the multitude of technologies to systematically measure multiple biological molecules simultaneously.

Precision

The closeness of repeated measurements to each other. High precision means that measurements are highly reproducible.

Accuracy

The closeness of the average of repeated measurements to the true value. High accuracy means that the measurements are on average in good agreement with the true quantity.

GC correction

A computational approach used to account for sequencing depth biases due to the guanine/cytosine composition of a particular region of the genome.

Shotgun proteomics

In ‘shotgun’ or ‘bottom-up’ proteomics, the proteins in a sample are cleaved into peptides before being analysed by mass spectrometry. Peptides are simpler than proteins, which facilitates their analysis by mass spectrometry and makes the shotgun approach particularly popular.

Proteases

Enzymes that digest proteins into smaller fragments. In shotgun proteomics, proteins are digested into peptides by sequence-specific proteases (such as trypsin, which cleaves proteins at the carboxy-terminal side of lysine and arginine residues).

Lipopolysaccharide

(LPS). A structural component of the outer membrane of Gram-negative bacteria. LPS may be sensed by specialized cells of the mammalian immune system (for example, dendritic cells), triggering both transcriptional and post-transcriptional responses so as to combat an imminent infection.

Transcription rates

The rates at which mRNA transcripts are generated for given genes.

Half-lives

The times it takes for a set of molecules (mRNAs and proteins in the context of this Review) to reduce in number to half of their original quantity via degradation. The term implies that degradation follows first-order kinetics, which is not always true.

Translation rate constants

The rates at which proteins are synthesized, as a function of transcript number (expressed as protein copies per mRNA per hour).

Secretomes

The complement of the proteome produced and secreted by cells.

Polarized cells

A difference in the distribution of cellular materials across a cell (for example, of organelles or proteins).

Maternal to zygotic transition

The point at which a developing zygote transitions from relying on maternally imparted proteins and mRNAs to gene products encoded by and transcribed from its own genome.

Erythropoiesis

The process involving the development and differentiation of red blood cells (erythrocytes).

Quiescent

Referring to quiescence, which is a cellular state occurring in most organisms that is characterized by a temporary exit from the cell cycle.

Quantitative trait loci

(QTLs). Loci in the genome for which the genotype correlates with variation in a quantifiable trait of an organism. Expression QTLs (eQTLs) and protein QTLs (pQTLs) are loci that correlate with variation in mRNA and protein levels, respectively.

Aneuploidy

The abnormal copy number of either a segment of or the entire chromosome in the genome.

Stoichiometry

With reference to protein complexes, the proportion of the individual subunits that make up a protein complex.

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Buccitelli, C., Selbach, M. mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet 21, 630–644 (2020). https://doi.org/10.1038/s41576-020-0258-4

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