Papers by Georgy Koentges
Disentangling networks of regulation of gene expression is a major challenge in the field of comp... more Disentangling networks of regulation of gene expression is a major challenge in the field of computational biology. Harvesting the information contained in microarray data sets is a promising approach towards this challenge. We propose an algorithm for the optimal estimation of Bayesian networks from microarray data, which reduces the CPU time and memory consumption of previous algorithms. We prove that the space complexity can be reduced from O(n(2) x 2(n)) to O(2(n)), and that the expected calculation time can be reduced from O(n(2) x 2(n)) to O(n x 2(n)), where n is the number of genes. We make intrinsic use of a limitation of the maximal number of regulators of each gene, which has biological as well as statistical justifications. The improvements are significant for some applications in research.
Development
To investigate the influence of hindbrain segmentation on craniofacial patterning we have studied... more To investigate the influence of hindbrain segmentation on craniofacial patterning we have studied the long term fate of neural crest (NC) subpopulations of individual rhombomeres (r), using quail-chick chimeras. Mapping of all skeletal and muscle connective tissues developing from these small regions revealed several novel features of the cranial neural crest. First, the mandibular arch skeleton has a composite origin in which the proximal elements are r1+r2 derived, whereas more distal ones are exclusively midbrain derived. The most proximal region of the lower jaw is derived from second arch (r4) NC. Second, both the lower jaw and tongue skeleton display an organisation which precisely reflects the rostrocaudal order of segmental crest deployment from the embryonic hindbrain. Third, cryptic intraskeletal boundaries, which do not correspond to anatomical landmarks, form sharply defined interfaces between r1+r2, r4 and r6+r7 crest. Cells that survive the early apoptotic elimination ...
Zoological Journal of the Linnean Society, 2005
Journal of Biological Chemistry, 2012
Background: DNA sequences called CRMs determine the precise patterns of gene expression. Results:... more Background: DNA sequences called CRMs determine the precise patterns of gene expression. Results: We identify and characterize the function of six novel hes1 CRMs. Conclusion: HES1 expression is controlled by multiple distal CRMs in addition to the known promoter. Significance: A powerful combination of computational and experimental methodologies enhances our knowledge of hes1 transcriptional control.
Bioinformatics, 2013
Motivation: cis-regulatory DNA sequence elements, such as enhancers and silencers, function to co... more Motivation: cis-regulatory DNA sequence elements, such as enhancers and silencers, function to control the spatial and temporal expression of their target genes. Although the overall levels of gene expression in large cell populations seem to be precisely controlled, transcription of individual genes in single cells is extremely variable in real time. It is, therefore, important to understand how these cis-regulatory elements function to dynamically control transcription at single-cell resolution. Recently, statistical methods have been proposed to back calculate the rates involved in mRNA transcription using parameter estimation of a mathematical model of transcription and translation. However, a major complication in these approaches is that some of the parameters, particularly those corresponding to the gene copy number and transcription rate, cannot be distinguished; therefore, these methods cannot be used when the copy number is unknown. Results: Here, we develop a hierarchical Bayesian model to estimate biokinetic parameters from live cell enhancer-promoter reporter measurements performed on a population of single cells. This allows us to investigate transcriptional dynamics when the copy number is variable across the population. We validate our method using synthetic data and then apply it to quantify the function of two known developmental enhancers in real time and in single cells. Availability: Supporting information is submitted with the article.
BMC Bioinformatics, 2007
Background S/MARs are regions of the DNA that are attached to the nuclear matrix. These regions a... more Background S/MARs are regions of the DNA that are attached to the nuclear matrix. These regions are known to affect substantially the expression of genes. The computer prediction of S/MARs is a highly significant task which could contribute to our understanding of chromatin organisation in eukaryotic cells, the number and distribution of boundary elements, and the understanding of gene regulation in eukaryotic cells. However, while a number of S/MAR predictors have been proposed, their accuracy has so far not come under scrutiny. Results We have selected S/MARs with sufficient experimental evidence and used these to evaluate existing methods of S/MAR prediction. Our main results are: 1.) all existing methods have little predictive power, 2.) a simple rule based on AT-percentage is generally competitive with other methods, 3.) in practice, the different methods will usually identify different sub-sequences as S/MARs, 4.) more research on the H-Rule would be valuable. Conclusion A new...
The neck and shoulder region of vertebrates has undergone a complex evolutionary history. To iden... more The neck and shoulder region of vertebrates has undergone a complex evolutionary history. To identify its underlying mechanisms we map the destinations of embryonic neural crest and mesodermal stem cells using Cre-recombinase- mediated transgenesis. The single-cell resolution of this genetic labelling reveals cryptic cell boundaries traversing the seemingly homogeneous skeleton of the neck and shoulders. Within this assembly of bones and muscles we discern a precise code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey as they form muscle scaffolds. The neural crest anchors the head onto the anterior lining of the shoulder girdle, while a Hox-gene- controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton. The skeleton that we identify as neural crest-derived is specifically affected in human Klippel-Feil syndrome, Sprengel's deformity and Arnold-Chiari I/II malformation, providing insights into their likely a...
Nature, 2008
The delightful Persian miniature of a composite elephant at the Aga Khan Trust for Culture in Gen... more The delightful Persian miniature of a composite elephant at the Aga Khan Trust for Culture in Geneva (Fig. 1) conveys such a concept. We understand that living things, such as the elephant, are complex and, fortunately, there is a bit more light around these days. ...
Plos One 6 Article E27886, Dec 15, 2011
The extraction of fluorescence time course data is a major bottleneck in high-throughput live-cel... more The extraction of fluorescence time course data is a major bottleneck in high-throughput live-cell microscopy. Here we present an extendible framework based on the open-source image analysis software ImageJ, which aims in particular at analyzing the expression of fluorescent reporters through cell divisions. The ability to track individual cell lineages is essential for the analysis of gene regulatory factors involved in the control of cell fate and identity decisions. In our approach, cell nuclei are identified using Hoechst, and a characteristic drop in Hoechst fluorescence helps to detect dividing cells. We first compare the efficiency and accuracy of different segmentation methods and then present a statistical scoring algorithm for cell tracking, which draws on the combination of various features, such as nuclear intensity, area or shape, and importantly, dynamic changes thereof. Principal component analysis is used to determine the most significant features, and a global parameter search is performed to determine the weighting of individual features. Our algorithm has been optimized to cope with large cell movements, and we were able to semi-automatically extract cell trajectories across three cell generations. Based on the MTrackJ plugin for ImageJ, we have developed tools to efficiently validate tracks and manually correct them by connecting broken trajectories and reassigning falsely connected cell positions. A gold standard consisting of two time-series with 15,000 validated positions will be released as a valuable resource for benchmarking. We demonstrate how our method can be applied to analyze fluorescence distributions generated from mouse stem cells transfected with reporter constructs containing transcriptional control elements of the Msx1 gene, a regulator of pluripotency, in mother and daughter cells. Furthermore, we show by tracking zebrafish PAC2 cells expressing FUCCI cell cycle markers, our framework can be easily adapted to different cell types and fluorescent markers.
Bioinformatics, Aug 9, 2010
Some recent comparative studies have revealed that regulatory regions can retain function over la... more Some recent comparative studies have revealed that regulatory regions can retain function over large evolutionary distances, even though the DNA sequences are divergent and difficult to align. It is also known that such enhancers can drive very similar expression patterns. This poses a challenge for the in silico detection of biologically related sequences, as they can only be discovered using alignment-free methods. Results: Here, we present a new computational framework called Regulatory Region Scoring (RRS) model for the detection of functional conservation of regulatory sequences using predicted occupancy levels of transcription factors of interest. We demonstrate that our model can detect the functional and/or evolutionary links between some non-alignable enhancers with a strong statistical significance. We also identify groups of enhancers that are likely to be similarly regulated. Our model is motivated by previous work on prediction of expression patterns and it can capture similarity by strong binding sites, weak binding sites and even the statistically significant absence of sites. Our results support the hypothesis that weak binding sites contribute to the functional similarity of sequences.
Science, 2002
In his poem about the lonely Maldive Shark, Herman Melville describes the daunting jaws of a se... more In his poem about the lonely Maldive Shark, Herman Melville describes the daunting jaws of a serious meat-eater, which serve as an asylum for the sleek little pilot fish, azure and slim, hiding in his jaws of the Fates. The jaws of the Fates may act rather unpredictably in the ...
Development, May 15, 1997
Neurotrophins signal through members of the trk family of tyrosine kinase receptors and are known... more Neurotrophins signal through members of the trk family of tyrosine kinase receptors and are known to regulate several neuronal properties. Although initially characterized by their ability to prevent naturally occurring cell death of subsets of neurons during development, neurotrophins can also regulate the proliferation and differentiation of precursor cells. Here we report a novel involvement of neurotrophins in early development of the neural tube. We demonstrate that a functional trkB receptor is expressed by motor neuron progenitors in the ventral neural tube and that treatment of ventral neural tube explants with the trkB ligand Brain-Derived Neurotrophic Factor (BDNF) leads to a significant increase in the number of motor neurons. The only BDNF expression detectable at this stage is by a subset of ventrally projecting interneurons in the dorsal neural tube; ablating this region in vivo leads to a reduction of motor neuron numbers. This loss can be prevented by simultaneous treatment with BDNF. We propose that BDNF produced by dorsal interneurons stimulates proliferation and/or differentiation of motor neuron progenitors after anterograde axonal transport and release in proximity to the trkB-expressing motor neuron precursors, thereby coordinating development between dorsal and ventral regions of the neural tube.
Genome Biology and Evolution, 2015
The process of transcription is highly stochastic leading to cell-to-cell variations and noise in... more The process of transcription is highly stochastic leading to cell-to-cell variations and noise in gene expression levels. However, key essential genes have to be precisely expressed at the correct amount and time to ensure proper cellular development and function. Studies in yeast and bacterial systems have shown that gene expression noise decreases as mean expression levels increase, a relationship that is controlled by promoter DNA sequence. However, the function of distal cis-regulatory modules (CRMs), an evolutionary novelty of metazoans, in controlling transcriptional robustness and variability is poorly understood. In this study, we used live cell imaging of transfected reporters combined with a mathematical modelling and statistical inference scheme, to quantify the function of conserved Msx1 CRMs and promoters in modulating single cell real time transcription rates in C2C12 mouse myoblasts. The results show that the mean expression-noise relationship is solely promoter controlled for this key pluripotency regulator. In addition, we demonstrate that CRMs modulate single cell basal promoter rate distributions in a graded manner across a population of cells. This extends the rheostatic model of CRM action to provide a more detailed understanding of CRM function at single cell resolution. We also identify a novel CRM transcriptional filter function that acts to reduce intracellular variability in transcription rates and show that this can be phylogenetically separable from rate modulating CRM activities. These results are important for understanding how the expression of key vertebrate developmental transcription factors is precisely controlled both within and between individual cells.
Science (New York, N.Y.), Jan 11, 2002
Uploads
Papers by Georgy Koentges