Divergence in cis-regulatory networks: taking the 'species' out of cross-species analysis

Significant differences between species in genomic occupancy of conserved transcription factors are mostly due to species-specificity of cis-regulatory sequences

Identification of tightly regulated groups of genes during Drosophila melanogaster embryogenesis

Time-series analysis of whole-genome expression data during Drosophila melanogaster development indicates that up to 86% of its genes change their relative transcript level during embryogenesis. By applying conservative filtering criteria and requiring ‘sharp' transcript changes, we identified 1534 maternal genes, 792 transient zygotic genes, and 1053 genes whose transcript levels increase during embryogenesis. Each of these three categories is dominated by groups of genes where all transcript levels increase and/or decrease at similar times, suggesting a common mode of regulation. For example, 34% of the transiently expressed genes fall into three groups, with increased transcript levels between 2.5–12, 11–20, and 15–20 h of development, respectively. We highlight common and distinctive functional features of these expression groups and identify a coupling between downregulation of transcript levels and targeted protein degradation. By mapping the groups to the protein network, we also predict and experimentally confirm new functional associations

Analysis of variation at transcription factor binding sites in Drosophila and humans

Background: Advances in sequencing technology have boosted population genomics and made it possible to map the positions of transcription factor binding sites (TFBSs) with high precision. Here we investigate TFBS variability by combining transcription factor binding maps generated by ENCODE, modENCODE, our previously published data and other sources with genomic variation data for human individuals and Drosophila isogenic lines. Results: We introduce a metric of TFBS variability that takes into account changes in motif match associated with mutation and makes it possible to investigate TFBS functional constraints instance-by-instance as well as in sets that share common biological properties. We also take advantage of the emerging per-individual transcription factor binding data to show evidence that TFBS mutations, particularly at evolutionarily conserved sites, can be efficiently buffered to ensure coherent levels of transcription factor binding. Conclusions: Our analyses provide insights into the relationship between individual and interspecies variation and show evidence for the functional buffering of TFBS mutations in both humans and flies. In a broad perspective, these results demonstrate the potential of combining functional genomics and population genetics approaches for understanding gene regulation.European Molecular Biology Laboratory (interdisciplinary fellowship (EIPOD))Deutsche Forschungsgemeinschaft (DFG FU 750/1-1

Predictive features of gene expression variation reveal mechanistic link with differential expression

Abstract For most biological processes, organisms must respond to extrinsic cues, while maintaining essential gene expression programmes. Although studied extensively in single cells, it is still unclear how variation is controlled in multicellular organisms. Here, we used a machine‐learning approach to identify genomic features that are predictive of genes with high versus low variation in their expression across individuals, using bulk data to remove stochastic cell‐to‐cell variation. Using embryonic gene expression across 75 Drosophila isogenic lines, we identify features predictive of expression variation (controlling for expression level), many of which are promoter‐related. Genes with low variation fall into two classes reflecting different mechanisms to maintain robust expression, while genes with high variation seem to lack both types of stabilizing mechanisms. Applying this framework to humans revealed similar predictive features, indicating that promoter architecture is an ancient mechanism to control expression variation. Remarkably, expression variation features could also partially predict differential expression after diverse perturbations in both Drosophila and humans. Differential gene expression signatures may therefore be partially explained by genetically encoded gene‐specific features, unrelated to the studied treatment

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation

International audienceX chromosome dosage compensation in Drosophila requires chromosome-wide coordination of gene activation. The male-specific lethal dosage compensation complex (DCC) identifies and binds to X-chromosomal high-affinity sites (HAS) from which it boosts transcription. A sub-class of HAS, PionX sites, represent first contacts on the X. Here, we explored the chromosomal interactions of representative PionX sites by high-resolution 4C and determined the global chromosome conformation by Hi-C in sex-sorted embryos. Male and female X chromosomes display similar nuclear architecture, concordant with clustered, constitutively active genes. PionX sites, like HAS, are evenly distributed in the active compartment and engage in short- and long-range interactions beyond compartment boundaries. Long-range, inter-domain interactions between DCC binding sites are stronger in males, suggesting that the complex refines chromatin organization. By de novo induction of DCC in female cells, we monitored the extent of activation surrounding PionX sites. This revealed a remarkable range of DCC action not only in linear proximity, but also at megabase distance if close in space, suggesting that DCC profits from pre-existing chromosome folding to activate genes