ewallace
commented
2 years ago DRAFT - updated 15 April discussing with folks
To the Editorial Board:
We invite you to consider our manuscript:
Limitations of composability of cis-regulatory elements in messenger RNA
for publication in Nucleic Acids Research as a standard research article. The manuscript takes a quantitative and conceptual approach to gene regulation using synthetic reporters, and so is suitable for the Synthetic Biology and Bioengineering subject category. We study the effects of composing biological parts to control gene regulation, using transcriptome-wide data analyses and principled statistical analysis of hundreds of reporter genes. Our results shows that:
- Terminator effects on gene expression depend on other cis-regulatory elements, in budding yeast
- Transcriptome-wide inferences of motif effects partially predict effects in synthetic genes
- Cis-regulatory motif effects on gene expression depend both on terminator context and promoter pairing
One innovation of our study is to quantify combinations of regulatory elements that are far apart, promoters and terminators that are separated by hundreds of nucleotides of coding sequence. This distinguishes it from other excellent studies by the groups of Eran Segal and others, that measure the effects of far larger numbers of variants but all in the same cis-regulatory context. The next innovation that builds on this is to compare quantification of cis-regulatory elements in transcriptome-wide studies with their effects inserted in a variety of reporter genes in various combinations. The work argues that these kinds of experiments will be important to understand the grammar of gene regulation, and thus to design synthetic genes with desired regulation.
We suggest reviewers who are expert in quantitative studies of gene expression regulation (Julien Gagneur, Magnus Rattray, Ian Sudbery) as well as in synthetic biology (Francesca Ceroni, Tom Howard). Julien Gagneur in particular would be ideal as our modeling approach builds directly on his work. We might also suggest experts in 3'UTR regulation and/or mRNA decay (Christine Mayr, Karsten Weis).
Yours sincerely, Edward Wallace, on behalf of all authors.
I will draft a cover letter to send to NAR, then run it by @DimmestP.