The precise timeline of transcriptional regulation reveals causation in mouse somitogenesis network

Abstract

BackgroundIn vertebrate development, the segmental pattern of the body axis is established as somites, masses of mesoderm distributed along the two sides of the neural tube, are formed sequentially in the anterior-posterior axis. This mechanism depends on waves of gene expression associated with the Notch, Fgf and Wnt pathways. The underlying transcriptional regulation has been studied by whole-transcriptome mRNA profiling; however, interpretation of the results is limited by poor resolution, noisy data, small sample size and by the absence of a wall clock to assign exact time for recorded points.ResultsWe present a method of Maximum Entropy deconvolution in both space and time and apply it to extract, from microarray timecourse data, the full spatiotemporal expression profiles of genes involved in mouse somitogenesis. For regulated genes, we have reconstructed the temporal profiles and determined the timing of expression peaks along the somite cycle to a single-minute resolution. Our results also indicate the presence of a new class of genes (including Raf1 and Hes7) with two peaks of activity in two distinct phases of the somite cycle. We demonstrate that the timeline of gene expression precisely reflects their functions in the biochemical pathways and the direction of causation in the regulatory networks.ConclusionsBy applying a novel framework for data analysis, we have shown a striking correspondence between gene expression times and their interactions and regulations during somitogenesis. These results prove the key role of finely tuned transcriptional regulation in the process. The presented method can be readily applied to studying somite formation in other datasets and species, and to other spatiotemporal processes.

The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis

“…Notch signaling plays a critical role in somite formation in developing vertebrate embryos, and changes in levels of Notch signaling during development result in disruption of the symmetric, bilaterally formed somites that can be readily observed in the zebrafish embryo(37,41–43) (Fig. 5E and 5F).…”

Predicting proteome dynamics using gene expression data

“…as are much longer than the step Δ t . In the case of very dynamic expression data (e.g Yeast Metabolic Cycle) 25 , where characteristic scale of the process is shorter, more advanced methods may need to be used to prepare input transcriptomic data for modeling proteome dynamics, such as our MaxEnt model-based approach to infer high-resolution changes in gene expression 13 , 26 , 27 .…”

A Conserved Structural Signature of the Homeobox Coding DNA in HOX genes

“…This double function could make the homeobox a perfect material for a logical element that has evolved into the basic building block of the circuitry encoding and executing the complex logic of developmental programs. Our discovery may provide a key step towards understanding the molecular basis for the colinearity and synchronization of Hox genes, the conserved synteny of other homeobox-containing transcription factors, and its relation to the intricately regulated somite clock 51 52 53 54 55 . The observed significance of HRC3 signature is significantly higher in anterior Hox genes than in posterior ones; if the motif is indeed involved in regulation of the Hox genes, such difference may be explained by the stronger conservation of the anterior body plan than posterior across the animal kingdom.…”