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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00571

Borders of cis-regulatory DNA sequences preferentially harbor the divergent transcription factor binding motifs in the human genome

  • 1Institute of Information Science, Academia Sinica, Taiwan

Changes in cis-regulatory DNA sequences and transcription factor (TF) repertoires provide major sources of phenotypic diversity that shape the evolution of gene regulation in eukaryotes. The DNA-binding specificities of TFs may be diversified or produce new variants in different eukaryotic species. However, it is currently unclear how various levels of divergence in TF DNA-binding specificities or motifs became introduced into the cis-regulatory DNA regions of the genome over evolutionary time. Here, we first estimated the evolutionary divergence levels of TF binding motifs and quantified their occurrence at DNase I-hypersensitive sites. Results from our in silico motif scan and experimentally derived chromatin immunoprecipitation (TF-ChIP) show that the divergent motifs tend to be introduced in the edges of cis-regulatory regions, which is probably accompanied by the expansion of the accessible core of promoter-associated regulatory elements during evolution. We also find that the genes neighboring the expanded cis-regulatory regions with the most divergent motifs are associated with functions like development and morphogenesis. Accordingly, we propose that the accumulation of divergent motifs in the edges of cis-regulatory regions provides a functional mechanism for the evolution of divergent regulatory circuits.

Keywords: transcription factor binding sites, motifs, cis-regulatory elements (CREs), TF binding specificities, open chromatins

Received: 06 Sep 2018; Accepted: 06 Nov 2018.

Edited by:

Alfredo Pulvirenti, Università degli Studi di Catania, Italy

Reviewed by:

Ka-Chun Wong, City University of Hong Kong, Hong Kong
Iros Barozzi, Imperial College London, United Kingdom  

Copyright: © 2018 Tsai, Huang, Kwan and Tsai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Huai-Kuang Tsai, Institute of Information Science, Academia Sinica, Nankang, Taiwan, hktsai@iis.sinica.edu.tw
Dr. Zing Tsung-Yeh Tsai, Institute of Information Science, Academia Sinica, Nankang, Taiwan, zing119@gmail.com