Normal cell functioning requires appropriate gene expression, which depends on multiple regulatory layers (see [1] for review). In this context, transcriptional regulatory modules (TRMs) were extensively studied (for instance [2,3,4,5]). By definition, a TRM is a set of genes for which transcriptional activity is modulated by a specific transcription factor (TF) [6]. In the model yeast Saccharomyces cerevisiae, TRMs are well described [2,3,4,5] and public databases like YEASTRACT [7] or SGD [8], provide lists of target genes for any TF. All together TRMs were explored to better understand their individual organizations, but also their collective relationships [4, 5, 9, 10]. In most studies, questions were addressed via a representation of TRMs as networks. In these networks, TF and target genes are the nodes, which are connected by directed edges (from TF to related targets). Topological properties of such networks were analysed to reveal the design principles underlying transcriptional regulations. It allowed the discovery of important regulatory motifs, surprisingly consistent across very different species [10, 11].
In addition to this information, spatial organization of the 16 chromosomes of S. cerevisiae was reported in the literature [1]. Experimental techniques derived from chromosome conformation capture (3C) were used to obtain a tridimensional (3D) model [12]. This model is based on the idea that interphase chromosomes are not positioned randomly within the nucleus. In particular, chromosomes should adopt a “Rabl configuration”, in which centromeres are clustered together at one pole of the nucleus, whereas arms are extended in several directions until telomeres, which are abutted to the nuclear envelope. Moreover, chromosome 12, which carries the rDNA repeats in S. cerevisiae, is expected to extend outward to join the nucleolus, i.e. the site of ribosome biogenesis (Additional file 1). This 3D model is relevant with the existence of a repressive chromatin structure, i.e. silent chromatin, which is known in yeasts for a long time (see [13] for a review) and affects mating-type loci, telomeres or rDNA repeats. More recently, this 3D model was used to study potential connections between interchromosomal DNA contacts and gene co-expressions [14]. Significant correlations were found, thus supporting the idea that a non-random nature of the genome organization helps to coordinate transcriptional processes in groups of genes, like those found in TRMs.
In this work, our aim was to search for additional insights into the organization of TRMs based on the 3D model of the S. cerevisiae genome at interphase. The TRMs were explored from a new perspective, which integrates functional and spatial information presently available, and addressed the following question: are target genes associated to a common TF (TRM) randomly disseminated within the nucleus, or are they preferentially co-localized? In the literature, this question was only partially answered, focusing essentially on spatial distances between genes coding for TFs and associated targets [15]. Our analysis represents an additional step in this context, reporting all distances between genes that belong to any TRM, as described in the latest release of the YEASTRACT database. Statistical parameters are provided, to quantify the intensity of potential bias observed in distributions of pairwise Euclidean distances calculated between lists of genes. A web tool called 3D-Scere (https://3d-scere.ijm.fr/) was also developed. With this tool, any researcher can retrieve information for all pairs of genes that belong to a list of his/her interest.