Codon usage is an important determinant of gene expression levels largely through its effects on transcription.
Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Zhipeng
Z
Zhou
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Yunkun
Y
Dang
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Mian
M
Zhou
National Institute of Biological Sciences, Changping District, Beijing 102206, China.
Lin
L
Li
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Chien-Hung
CH
Yu
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Jingjing
J
Fu
National Institute of Biological Sciences, Changping District, Beijing 102206, China.
She
S
Chen
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; yi.liu@utsouthwestern.edu.
Yi
Y
Liu
D001482:Base Composition; D003062:Codon; D005786:Gene Expression Regulation; D016681:Genome, Fungal; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D009491:Neurospora / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic
D003062:Codon; D006657:Histones; D012333:RNA, Messenger; D012319:RNA Polymerase II
Neurospora; codon usage; transcription
Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8948-53
22615360
Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):E1362-71
26903634
EMBO J. 2016 Oct 4;35(19):2087-2103
27436874
Mol Syst Biol. 2014 Dec 23;10:770
25538139
Nat Rev Genet. 2011 Jan;12(1):32-42
21102527
Cell. 2009 Sep 18;138(6):1236-46
19747717
Science. 2013 Dec 13;342(6164):1367-72
24337295
Heredity (Edinb). 2010 Jul;105(1):38-44
20407471
Genetics. 1994 Mar;136(3):927-35
8005445
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4867-74
24277852
Eukaryot Cell. 2008 Jan;7(1):28-37
17766461
Cell. 2008 Jul 25;134(2):341-52
18662548
Genome Res. 2009 Mar;19(3):427-37
19092133
Annu Rev Genet. 2008;42:287-99
18983258
Science. 2009 Apr 10;324(5924):255-8
19359587
Genes Dev. 2015 Mar 1;29(5):526-37
25691092
G3 (Bethesda). 2012 Oct;2(10):1207-12
23050231
Nature. 2014 Oct 30;514(7524):650-3
25132551
Genetics. 2009 May;182(1):11-23
19171944
EMBO Rep. 2013 Oct;14(10):923-30
23958634
Mol Cell. 2016 Mar 17;61(6):874-85
26990990
Mol Cell Proteomics. 2005 Sep;4(9):1265-72
15958392
Nucleic Acids Res. 2014 Apr;42(6):3551-64
24413563
Nucleic Acids Res. 1986 Jul 11;14(13):5125-43
3526280
Fungal Genet Biol. 2004 Oct;41(10):897-910
15341912
PLoS Genet. 2013;9(9):e1003761
24039604
Science. 1994 Mar 18;263(5153):1578-84
8128244
Mol Cell. 2015 Jul 16;59(2):149-61
26186290
Science. 2002 Aug 2;297(5582):815-9
12098706
Nat Struct Mol Biol. 2014 Dec;21(12):1100-5
25420103
Genes Dev. 2000 Oct 1;14(19):2452-60
11018013
Genes Cells. 2009 Apr;14(4):499-509
19335619
Genes Dev. 2007 Dec 15;21(24):3283-95
18079175
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8310-5
20404183
J Biol Chem. 1982 Mar 25;257(6):3026-31
7037777
Science. 1993 Dec 10;262(5140):1724-8
8259516
Mol Microbiol. 2015 Sep;97(5):974-87
26032251
Mol Biol Evol. 2009 Jul;26(7):1571-80
19349643
Cell. 1997 May 2;89(3):469-76
9150146
Genes Dev. 2012 Oct 1;26(19):2119-37
23028141
Cell Rep. 2014 Sep 25;8(6):2015-30
25220462
Cell. 2010 Apr 16;141(2):344-54
20403328
Fungal Genet Biol. 2003 Apr;38(3):327-32
12684022
EMBO J. 2001 Jan 15;20(1-2):101-8
11226160
PLoS Genet. 2012;8(3):e1002603
22479199
Nature. 2001 Nov 15;414(6861):277-83
11713521
Genetics. 2004 Jul;167(3):1293-304
15280243
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9430-5
9689097
PLoS Biol. 2006 Jun;4(6):e180
16700628
Genetics. 1998 Aug;149(4):1787-97
9691037
Fungal Genet Biol. 1997 Jun;21(3):258-66
9290240
Proc Natl Acad Sci U S A. 1985 Aug;82(16):5450-4
2991927
Nature. 2016 Jan 21;529(7586):358-63
26760206
Nat Protoc. 2012 Mar 01;7(3):562-78
22383036
Cell. 2015 Mar 12;160(6):1111-24
25768907
Mol Syst Biol. 2011 Apr 12;7:481
21487400
PLoS Genet. 2010 Sep 23;6(9):e1001132
20885793
Mol Cell Biol. 1996 Feb;16(2):513-21
8552078
J Biol Chem. 2011 Apr 1;286(13):11469-78
21300798
PLoS One. 2009 Apr 21;4(4):e5286
19461939
Fungal Genet Biol. 2007 May;44(5):307-14
17320431
Mol Cell. 2015 Sep 3;59(5):744-54
26321254
Nature. 2006 Mar 23;440(7083):561-4
16554824
Nature. 2013 Mar 7;495(7439):111-5
23417067
Nat Struct Mol Biol. 2013 Feb;20(2):237-43
23262490
J Mol Biol. 2012 Sep 21;422(3):328-35
22705285
PLoS Genet. 2012;8(5):e1002712
22589747
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4482-7
10200288
Mol Biol Evol. 1985 Jan;2(1):13-34
3916708