Evidence that alternative transcriptional initiation is largely nonadaptive.

Chuan Xu,Joong-Ki Park,Jianzhi Zhang,Laurence D Hurst

doi:10.1371/journal.pbio.3000197

Abstract

Alternative transcriptional initiation (ATI) refers to the frequent observation that one gene has multiple transcription start sites (TSSs). Although this phenomenon is thought to be adaptive, the specific advantage is rarely known. Here, we propose that each gene has one optimal TSS and that ATI arises primarily from imprecise transcriptional initiation that could be deleterious. This error hypothesis predicts that (i) the TSS diversity of a gene reduces with its expression level; (ii) the fractional use of the major TSS increases, but that of each minor TSS decreases, with the gene expression level; and (iii) cis-elements for major TSSs are selectively constrained, while those for minor TSSs are not. By contrast, the adaptive hypothesis does not make these predictions a priori. Our analysis of human and mouse transcriptomes confirms each of the three predictions. These and other findings strongly suggest that ATI predominantly results from molecular errors, requiring a major revision of our understanding of the precision and regulation of transcription.

Highlights

The transcription start site (TSS) is the first nucleotide transcribed in a run of transcription, while the surrounding genomic region of the transcription start sites (TSSs) is often referred to as the core promoter [1]
Many researchers believe that this phenomenon is adaptive because it allows production of multiple transcripts, from the same gene, that potentially vary in function or posttranscriptional regulation
It is possible that each gene has only one optimal transcription start site and that alternative transcriptional initiation arises primarily from molecular errors that are slightly deleterious

Summary

Introduction

The transcription start site (TSS) is the first nucleotide transcribed in a run of transcription, while the surrounding genomic region of the TSS is often referred to as the core promoter [1]. The transcription of a gene may start from one of several TSSs, a phenomenon known as alternative transcriptional initiation (ATI); the different core promoters used are referred to as alternative promoters [8, 9]. One example is the human runt-related transcription factor 1 gene RUNX1, which can be transcribed from two different TSSs; the mRNA produced from the distal TSS mediates cap-dependent translation, whereas that from the proximal TSS contains a functional internal ribosome entry site (IRES) and mediates cap-independent translation [15]. Human LEF1, encoding lymphoid enhancer binding factor 1 that regulates the transcription of Wingless/Integrated (Wnt)/β-catenin genes, produces two different protein isoforms by using alternative TSSs; the longer isoform recruits β-catenin to Wnt target genes, whereas the shorter isoform cannot interact with β-catenin and instead suppresses the Wnt regulation of target genes [16]

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