Explore features of DNA sequences in orchestrating cis-regulation
Background
1) Numerous DNA regulatory elements in our genomes orchestrate gene expression activities.
2) The majority of these elements have limited evidence for conservation hence investigating their roles have been difficult.
3) Although profiling biochemical markers including histone modifications and DNA methylation can provide a snapshot of the amount of regulatory activities in our genomes, there is limited understanding of the amount of such activities that we are expected to find by chance.
Objectives
Our objective is to 1) create a genomic null hypothesis by quantifying the gene expression activity of evolutionarily distant DNA in yeast and computational prediction of random DNA activities in human cells and tissues. In parallel, we are 2) studying the effect of DNA regulatory sequences on impacting gene transcription in human embryonic stem cells (hESC) using massively paralleled reporter assays.
Results
In yeast, we found that >99% of bases in naïve DNA expressed as part of one or more transcripts.
In humans, we found that, while random DNA is predicted to have minimal activity, dinucleotide content-matched randomized DNA is predicted to have much of the regulatory activity of evolved sequences.
Manuscript
Luthra, I.†, Chen, X. E.†, Jensen, C.†, Rafi, A. M., Salaudeen, A. L., & de Boer, C. G. (2022). Biochemical activity is the default DNA state in eukaryotes. bioRxiv. 10.1101/2022.12.16.520785