Prediction of a key role of motifs binding E2F and NR2F in down-regulation of numerous genes during the development of the mouse hippocampus

Michal Dabrowski,Bozena Kaminska,Stein Aerts

doi:10.1186/1471-2105-7-367

Abstract

BackgroundWe previously demonstrated that gene expression profiles during neuronal differentiation in vitro and hippocampal development in vivo were very similar, due to a conservation of the important second singular value decomposition (SVD) mode (Mode 2) of expression. The conservation of Mode 2 suggests that it reflects a regulatory mechanism conserved between the two systems. In either dataset, the expression vectors of all the genes form two large clusters that differ in the sign of the contribution of Mode 2, which for the majority of them reflects the difference between down- or up-regulation.ResultsIn the current work, we used a novel approach of analyzing cis-regulation of gene expression in a subspace of a single SVD mode of temporal expression profiles. In the putative upstream regulatory sequences identified by mouse-human homology for all the genes represented in either dataset, we searched for simple features (motifs and pairs of motifs) associated with either sign of the loading of Mode 2. Using a cross-system training-test set approach, we identified E2F binding sites as predictors of down-regulation of gene expression during hippocampal development. NR2F binding sites, for the transcription factors Nr2f/COUP and Hnf4, and also NR2F_SP1 pairs of binding sites, were predictors of down-regulation of expression both during hippocampal development and neuronal differentiation. Analysis of another dataset, from gene profiling of myoblast differentiation in vitro, shows that the conservation of Mode 2 extends to the differentiation of mesenchymal cells. This permitted the identification of two more pairs of motifs, one of which included the CDE/CHR tandem element, as features associated with down-regulation both in the differentiating myoblasts and in the developing hippocampus. Of the features we identified, the E2F and CDE/CHR motifs may be associated with the cycling progenitor cell status, while NR2F may be related to the entry into differentiation along the neuronal pathway.ConclusionOur results constitute the first prediction of an expression pattern from the genomic sequence for the developing mammalian brain, and demonstrate a potential for the analysis of gene regulation in a subspace of a single SVD mode of expression.

Highlights

Introduction to linear algebraWellesley MA, Wellesley-Cambridge Press; 1993.19
Our results constitute the first prediction of an expression pattern from the genomic sequence for the developing mammalian brain, and demonstrate a potential for the analysis of gene regulation in a subspace of a single singular value decomposition (SVD) mode of expression
We evaluated its association with the sign of Mode 2, by calculating the probability of the split of the set of coding sequences (CNSs) harboring this feature between the sets of CNSs assigned to either sign of the loading of Mode 2

Summary

Introduction

Introduction to linear algebraWellesley MA, Wellesley-Cambridge Press; 1993.19. Alter O, Brown PO, Botstein D: Singular value decomposition for genome-wide expression data processing and modeling. We previously demonstrated that gene expression profiles during neuronal differentiation in vitro and hippocampal development in vivo were very similar, due to a conservation of the important second singular value decomposition (SVD) mode (Mode 2) of expression. The motifs present in corresponding cis-regulatory sequences of orthologous genes are often the same, but their precise arrangement may be changed [9,10]. Such conserved motifs are more likely to correspond to functional motifs, namely transcription factor binding sites [11]. Pairs of closely situated conserved motifs are attractive candidate features, as pairs of closely situated transcription factor binding sites were postulated to constitute minimal units or "composite elements" contributing to specific patterns of gene regulation [12,13]

Methods

Results

Discussion

Conclusion