Article

Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution.

Science (Impact Factor: 31.48). 12/2013; 342(6164):1367-1372. DOI: 10.1126/science.1243490
Source: PubMed

ABSTRACT Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons ("duons") that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias. Conversely, the regulatory code has been selectively depleted of TFs that recognize stop codons. More than 17% of single-nucleotide variants within duons directly alter TF binding. Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution.

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    • "(Stergachis et al., 2013; Weatheritt and Babu, 2013 "
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    • "To date, the role of gene body methylation remains unclear, although intriguing correlations have been identified related to differential promoter use and alternative splicing (Maunakea et al., 2010; Shukla et al., 2011). The recent discovery of dual-use codons (duons) for transcription factor binding generates further possible regulatory roles for cytosine modifications in gene bodies, as it could impact transcription factor binding (Stergachis et al., 2013). In this regard, our BGS and TAB-BGS results from the HOXA9 locus showing elevated 5hmC focused specifically at an exon-intron junction upon depletion of DNMT3B are intriguing. "
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    • "This phenomenon has been termed codon usage bias (CUB), and many studies support a role of natural selection in this phenomenon (Shields et al. 1988; Moriyama and Hartl 1993; Akashi et al. 1998; Comeron and Kreitman 1998; Chamary et al. 2006; Plotkin and Kudla 2011; Waldman et al. 2011; Behura et al. 2013; Kober and Pogson 2013). Proposed mechanisms influencing CUB include translational efficiency (Grantham et al. 1981; Ikemura 1985; Bulmer 1991; Carlini and Stephan 2003; Rocha 2004; Stoletzki and Eyre-Walker 2007; Parmley and Huynen 2009; Hense 2010; Ran and Higgs 2010, 2012; Sharp et al. 2010; Behura and Severson 2011; Shah and Gilchrist 2011; Qian et al. 2012; Agashe et al. 2013; Lawrie et al. 2013; Michely 2013), mRNA stability or folding (Moriyama and Powell 1998; dos Reis et al. 2004; Chamary and Hurst 2005; Chamary et al. 2006; Novoa and Ribas de Pouplana 2012; Kober and Pogson 2013; Shabalina et al. 2013), transcription factor binding (Stergachis 2013), overlap with other functional elements in the genome (Lin 2011), and/or a trade-off between rapid versus accurate translation (Yang et al. 2014). The level of CUB varies dramatically across species (Grantham et al. 1980a,b; Sharp 1988), including insects (Vicario et al. 2007), mammals (Doherty and McInerney 2013), and plants (Ingvarsson 2008, 2010). "
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