Similarity regression predicts evolution of transcription factor sequence specificity

First author: Samuel A. Lambert; Affiliations: University of Toronto (多伦多大学): Toronto, Canada

Corresponding author: Timothy R. Hughes 

Transcription factor (TF) binding specificities (motifs) are essential for the analysis of gene regulation. Accurate prediction of TF motifs is critical, because it is infeasible to assay all TFs in all sequenced eukaryotic genomes. There is ongoing controversy regarding the degree of motif diversification among related species that is, in part, because of uncertainty in motif prediction methods. Here we describe similarity regression, a significantly improved method for predicting motifs, which we use to update and expand the Cis-BP database. Similarity regression inherently quantifies TF motif evolution, and shows that previous claims of near-complete conservation of motifs between human and Drosophila are inflated, with nearly half of the motifs in each species absent from the other, largely due to extensive divergence in C2H2 zinc finger proteins. We conclude that diversification in DNA-binding motifs is pervasive, and present a new tool and updated resource to study TF diversity and gene regulation across eukaryotes.

在转录因子结合特异性（motif）对于分析基因的调控是十分重要的。因为在所有已测序的真核生物中，我们不可能用实验验证所有的转录因子，因此精确预测转录因子的motif至关重要。目前，对于近缘物种之间转录因子motif的分化程度还存在争议，部分是由于目前motif预测方法的不确定性所导致的。本文中，作者报道了一个相似性回归的新方法，该方法能够极大提升预测motif的能力，作者用该方法升级并更新了Cis-BP数据库。相似性回归能够帮助我们来量化转录因子motif的演化，结果显示之前我们过高估计了人类和果蝇之间motif的保守性，真正的结果是大概每个物种中有大概一半的motif在另一个物种中是不存在的，这其中大部分是C2H2锌指蛋白的分化导致的。作者在本文中发现DNA结合mitif的分化是普遍的，并且提供了一个新的工具帮助我们更好地研究不同真核生物间转录因子多样性和基因调控。

通讯：Timothy R. Hughes（http://www.moleculargenetics.utoronto.ca/faculty/2014/9/30/timothy-hughes）

个人简介：爱荷华大学，学士；贝勒医学院，博士；美国罗赛特制药公司，博士后。

研究方向：通过蛋白-DNA以及蛋白-RNA序列特异性来研究真核生物细胞是如何识别并解释基因组的信息的。

doi: https://doi.org/10.1038/s41588-019-0411-1

Journal: Nature Genetics

Published date: May 27, 2019