Computational exploration of cis-regulatory modules in rhythmic expression data using the “Exploration of Distinctive CREs and CRMs” (EDCC) and “CRM Network Generator” (CNG) programs

Abstract

Understanding the effect of cis-regulatory elements (CRE) and clusters of CREs, which are called cis-regulatory modules (CRM), in eukaryotic gene expression is a challenge of computational biology. We developed two programs that allow simple, fast and reliable analysis of candidate CREs and CRMs that may affect specific gene expression and that determine positional features between individual CREs within a CRM. The first program, "Exploration of Distinctive CREs and CRMs" (EDCC), correlates candidate CREs and CRMs with specific gene expression patterns. For pairs of CREs, EDCC also determines positional preferences of the single CREs in relation to each other and to the transcriptional start site. The second program, "CRM Network Generator" (CNG), prioritizes these positional preferences using a neural network and thus allows unbiased rating of the positional preferences that were determined by EDCC. We tested these programs with data from a microarray study of circadian gene expression in Arabidopsis thaliana. Analyzing more than 1.5 million pairwise CRE combinations, we found 22 candidate combinations, of which several contained known clock promoter elements together with elements that had not been identified as relevant to circadian gene expression before. CNG analysis further identified positional preferences of these CRE pairs, hinting at positional information that may be relevant for circadian gene expression. Future wet lab experiments will have to determine which of these combinations confer daytime specific circadian gene expression.

CRISPR/Cas9 and FLP-FRT mediated regulatory dissection of the BX-C of Drosophila melanogaster

“…The ne-tuning of expression of a gene is performed by several cis-regulatory DNA elements that include initiator elements, enhancers, repressors, Polycomb/trithorax response elements and promoter targeting sequences (Zhou and Levine 1999; Gaston and Jayaraman 2003; Ringrose and Paro 2004; Narlikar and Ovcharenko 2009; Iampietro et al 2010;Crocker et al 2016). In Drosophila melanogaster genome, these elements are often populated in 15-20 Kb regions that regulate the activity of associated genes (Ho et al 2009; Bekiaris et al 2018). Such regions where several CREs populate together and are responsible for the expression of a gene in a cell, tissue, or segment-speci c manner are called cis-regulatory modules (CRMs) (Ho et al 2009;Starr et al 2011;Bekiaris et al 2018).…”

“…In Drosophila melanogaster genome, these elements are often populated in 15-20 Kb regions that regulate the activity of associated genes (Ho et al 2009; Bekiaris et al 2018). Such regions where several CREs populate together and are responsible for the expression of a gene in a cell, tissue, or segment-speci c manner are called cis-regulatory modules (CRMs) (Ho et al 2009;Starr et al 2011;Bekiaris et al 2018). Plentiful studies have been dedicated towards understanding the role of many of these elements individually (Cléard et al 2006 ).…”

CRISPR/Cas9 and FLP-FRT mediated multi-modular engineering of the cis-regulatory landscape of the bithorax complex of Drosophila melanogaster

“…In Drosophila melanogaster genome, these elements are often populated in 15-20 Kb regions that regulate the activity of associated genes. Such regions where several CREs populate together and are responsible for the expression of a gene in a cell, tissue, or segment-specific manner are called cis -regulatory modules (CRMs) (Ho et al 2009; Starr et al 2011; Bekiaris et al 2018). Plentiful studies have been dedicated towards understanding the role of each of these elements individually (Polychronidou and Lohmann 2013; Kyrchanova et al 2011; Cléard et al 2006; Akbari et al 2008; Narlikar and Ovcharenko 2009).…”

CRISPR/Cas9 and FLP-FRT mediated multi-modular engineering of the cis-regulatory landscape of the bithorax complex of Drosophila melanogaster

“…The ne-tuning of expression of a gene is performed by several cis-regulatory DNA elements that include initiator elements, enhancers, repressors, Polycomb/trithorax response elements and promoter targeting sequences (Zhou and Levine 1999; Gaston and Jayaraman 2003; Ringrose and Paro 2004; Narlikar and Ovcharenko 2009; Iampietro et al 2010;Crocker et al 2016). In Drosophila melanogaster genome, these elements are often populated in 15-20 Kb regions that regulate the activity of associated genes (Ho et al 2009; Bekiaris et al 2018). Such regions where several CREs populate together and are responsible for the expression of a gene in a cell, tissue, or segment-speci c manner are called cis-regulatory modules (CRMs) (Ho et al 2009;Starr et al 2011;Bekiaris et al 2018).…”