Systematic analysis of transcription start sites in avian development

PLoS Biol. 2017 Sep 5;15(9):e2002887. doi: 10.1371/journal.pbio.2002887. eCollection 2017 Sep.

Abstract

Cap Analysis of Gene Expression (CAGE) in combination with single-molecule sequencing technology allows precision mapping of transcription start sites (TSSs) and genome-wide capture of promoter activities in differentiated and steady state cell populations. Much less is known about whether TSS profiling can characterize diverse and non-steady state cell populations, such as the approximately 400 transitory and heterogeneous cell types that arise during ontogeny of vertebrate animals. To gain such insight, we used the chick model and performed CAGE-based TSS analysis on embryonic samples covering the full 3-week developmental period. In total, 31,863 robust TSS peaks (>1 tag per million [TPM]) were mapped to the latest chicken genome assembly, of which 34% to 46% were active in any given developmental stage. ZENBU, a web-based, open-source platform, was used for interactive data exploration. TSSs of genes critical for lineage differentiation could be precisely mapped and their activities tracked throughout development, suggesting that non-steady state and heterogeneous cell populations are amenable to CAGE-based transcriptional analysis. Our study also uncovered a large set of extremely stable housekeeping TSSs and many novel stage-specific ones. We furthermore demonstrated that TSS mapping could expedite motif-based promoter analysis for regulatory modules associated with stage-specific and housekeeping genes. Finally, using Brachyury as an example, we provide evidence that precise TSS mapping in combination with Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-on technology enables us, for the first time, to efficiently target endogenous avian genes for transcriptional activation. Taken together, our results represent the first report of genome-wide TSS mapping in birds and the first systematic developmental TSS analysis in any amniote species (birds and mammals). By facilitating promoter-based molecular analysis and genetic manipulation, our work also underscores the value of avian models in unravelling the complex regulatory mechanism of cell lineage specification during amniote development.

MeSH terms

  • Animals
  • Biological Evolution
  • Chick Embryo
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Embryonic Development*
  • Genome-Wide Association Study*
  • Transcription Initiation Site*

Grants and funding

Ministry of Education, Culture, Sports, Science and Technology, Japan http://www.mext.go.jp/en/. Innovative Cell Biology by Innovative Technology (Cell Innovation Program) to Yoshihide Hayashizaki. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministry of Education, Culture, Sports, Science and Technology, Japan http://www.mext.go.jp/en/ to RIKEN Preventive Medicine and Diagnosis Innovation Program (Yoshihide Hayashizaki). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministry of Education, Culture, Sports, Science and Technology, Japan http://www.mext.go.jp/en/ to RIKEN Omics Science Center (Yoshihide Hayashizaki). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministry of Education, Culture, Sports, Science and Technology, Japan http://www.mext.go.jp/en/ to RIKEN Center for Life Science Technologies. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Russian Science Foundation grant for international groups (grant number 14-44-00022) to Oleg Gusev. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Russian Government Program of Competitive Growth of Kazan Federal University. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Takeda Science Foundation http://www.takeda-sci.or.jp/ to Guojun Sheng. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Kumamoto University IRCMS http://ircms.kumamoto-u.ac.jp/ to Guojun Sheng. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. RIKEN Center for Developmental Biology http://www.cdb.riken.jp/ to Guojun Sheng. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.