Phylogenetic Analysis of Cell Types using Histone Modifications

In cell differentiation, a cell of a less specialized type becomes one of a more specialized type, even though all cells have the same genome. Transcription factors and epigenetic marks like histone modifications can play a significant role in the differentiation process. In this paper, we present a simple analysis of cell types and differentiation paths using phylogenetic inference based on ChIP-Seq histone modification data. We propose new data representation techniques and new distance measures for ChIP-Seq data and use these together with standard phylogenetic inference methods to build biologically meaningful trees that indicate how diverse types of cells are related. We demonstrate our approach on H3K4me3 and H3K27me3 data for 37 and 13 types of cells respectively, using the dataset to explore various issues surrounding replicate data, variability between cells of the same type, and robustness. The promising results we obtain point the way to a new approach to the study of cell differentiation.Comment: Peer-reviewed and presented as part of the 13th Workshop on Algorithms in Bioinformatics (WABI2013

Probabilistic partitioning methods to find significant patterns in ChIP-Seq data

Motivation: We have witnessed an enormous increase in ChIP-Seq data for histone modifications in the past few years. Discovering significant patterns in these data is an important problem for understanding biological mechanisms. Results: We propose probabilistic partitioning methods to discover significant patterns in ChIP-Seq data. Our methods take into account signal magnitude, shape, strand orientation and shifts. We compare our methods with some current methods and demonstrate significant improvements, especially with sparse data. Besides pattern discovery and classification, probabilistic partitioning can serve other purposes in ChIP-Seq data analysis. Specifically, we exemplify its merits in the context of peak finding and partitioning of nucleosome positioning patterns in human promoters. Availability and implementation: The software and code are available in the supplementary material. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Low molecular mass dinitrosyl nonheme-iron complexes up-regulate noradrenaline release in the rat tail artery

BACKGROUND: Dinitrosyl nonheme-iron complexes can appear in cells and tissues overproducing nitric oxide. It is believed that due to their chemical nature these species may be implicated in certain pathophysiological events. We studied the possible role of low molecular mass dinitrosyl iron complexes in the control of noradrenaline release in electrically stimulated rat tail artery. RESULTS: A model complex, dinitrosyl-iron-thiosulfate (at 1–10 μM) produced a concentration-dependent enhancement of electrical field stimulated [(3)H]noradrenaline release (up to 2 fold). At the same time, dinitrosyl-iron-thiosulfate inhibited neurogenic vasoconstriction, consistent with its nitric oxide donor properties. A specific inhibitor of cyclic GMP dependent protein kinase, Rp-8pCPT-cGMPS, partially inhibited the effect of dinitrosyl-iron-thiosulfate on neurogenic vasoconstriction, but not on [(3)H]noradrenaline release. Another model complex, dinitrosyl-iron-cysteine (at 3 μM) elicited similar responses as dinitrosyl-iron-thiosulfate. Conventional NO and NO+ donors such as sodium nitroprusside, S-nitroso-L-cysteine or S-nitroso-glutathione (at 10 μM) had no effect on [(3)H]noradrenaline release, though they potently decreased electrically-induced vasoconstriction. The "false complex", iron(II)-thiosulfate showed no activity. CONCLUSIONS: Low molecular mass iron dinitrosyl complexes can up-regulate the stimulation-evoked release of vascular [(3)H]noradrenaline, apparently independently of their NO donor properties. This finding may have important implications in inflammatory tissues

ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries

The advent of high-throughput technologies such as ChIP-seq has made possible the study of histone modifications. A problem of particular interest is the identification of regions of the genome where different cell types from the same organism exhibit different patterns of histone enrichment. This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites. The software for this work can be downloaded from http://lcbb.epfl.ch/software.html

Study of cell differentiation by phylogenetic analysis using histone modification data

Background: In cell differentiation, a cell of a less specialized type becomes one of a more specialized type, even though all cells have the same genome. Transcription factors and epigenetic marks like histone modifications can play a significant role in the differentiation process.Results: In this paper, we present a simple analysis of cell types and differentiation paths using phylogenetic inference based on ChIP-Seq histone modification data. We precisely defined the notion of cell-type trees and provided a procedure of building such trees. We propose new data representation techniques and distance measures for ChIP-Seq data and use these together with standard phylogenetic inference methods to build biologically meaningful cell-type trees that indicate how diverse types of cells are related. We demonstrate our approach on various kinds of histone modifications for various cell types, also using the datasets to explore various issues surrounding replicate data, variability between cells of the same type, and robustness. We use the results to get some interesting biological findings like important patterns of histone modification changes during cell differentiation process.Conclusions: We introduced and studied the novel problem of inferring cell type trees from histone modification data. The promising results we obtain point the way to a new approach to the study of cell differentiation. We also discuss how cell-type trees can be used to study the evolution of cell types

New data on the Valanginian - Hauterivian Ammonites from the stratotypical area of Neuchâtel (Swiss Jura Mountains) : biostratigraphic implications

Lower Hauterivian ammonites yield precisions about the biostratigraphical scheme of the Lower Cretaceous in the stratotypical area of Neuchâtel (Swiss Jura Mountains). Thus, Stoicoceras pitrei (BUSNARDO, 1966) from the "Calcaire roux limoniteux" is reported in the upper Saynoceras verru-cosum Biozone (Karakaschiceras pronecostatum Subzone) of the Upper Valanginian. In the Lower Hau-terivian, Olcostephanus (O.) variegatus PAQUIER, 1900, from the upper part of the "Marnes bleues d'Hauterive" and Saynella cf. clypeiformis (d'ORBIGNY, 1841) from the "Marnes d'Uttins" (top of the lower part of the "Pierre jaune de Neuchâtel") extend greatly the range of the Lyticoceras nodosoplica-tum Biozone compared to a more reduced Crioceratites loryi Biozone indicated by Saynella neocomien-sis (BAUMBERGER, 1905) and a unique specimen of Crioceratites cf. gr. loryi (SARKAR, 1955) found in 1907.De nouvelles données sur les ammonites du Valanginien supérieur - Hauterivien inférieur apportent des précisions sur le schéma biostratigraphique du Crétacé inférieur de la région stratotypi-que de Neuchâtel (Jura suisse). Ainsi, Stoicoceras pitrei (BUSNARDO, 1966) du Calcaire roux limoniteux peut être rapportée à la partie supérieure de la biozone à Saynoceras verrucosum (sous-zone à Kara-kaschiceras pronecostatum) du Valanginien supérieur. Dans l'Hauterivien inférieur, Olcostephanus (O.) variegatus PAQUIER, 1900, de la partie supérieure des Marnes bleues d'Hauterive et Saynella cf. clypei-formis (d'ORBIGNY, 1841) des Marnes d'Uttins (sommet de la partie inférieure de la Pierre jaune de Neuchâtel) élargissent l'extension de la biozone à Lyticoceras nodosoplicatum par rapport à la biozone à Crioceratites loryi indiquée par Saynella neocomiensis (BAUMBERGER, 1905) et un unique spécimen de Crioceratites cf. gr. loryi (SARKAR, 1955) trouvé en 1907

Contribution of a tyrosine-based motif to cellular trafficking of wild-type and truncated NPY Y(1) receptors.

peer reviewedThe human NPY Y(1) receptor undergoes fast agonist-induced internalization via clathrin-coated pits then recycles back to the cell membrane. In an attempt to identify the molecular determinants involved in this process, we studied several C-terminal truncation mutants tagged with EFGP. In the absence of agonist, Y(1) receptors lacking the last 32 C-terminal amino acids (Y(1)Delta32) are constitutively internalized, unlike full-length Y(1) receptors. At steady state, internalized Y(1)Delta32 receptors co-localize with transferrin, a marker of early and recycling endosomes. Inhibition of constitutive internalization of Y(1)Delta32 receptors by hypertonic sucrose or by co-expression of Rab5aS34N, a dominant negative form of the small GTPase Rab5a or depletion of all three isoforms of Rab5 indicates the involvement of clathrin-coated pits. In contrast, a truncated receptor lacking the last 42 C-terminal amino acids (Y(1)Delta42) does not constitutively internalize, consistent with the possibility that there is a molecular determinant responsible for constitutive internalization located in the last 10 amino acids of Y(1)Delta32 receptors. We show that the agonist-independent internalization of Y(1)Delta32 receptors involves a tyrosine-based motif YXXPhi. The potential role of this motif in the behaviour of full-length Y(1) receptors has also been explored. Our results indicate that a C-terminal tyrosine-based motif is critical for the constitutive internalization of truncated Y(1)Delta32 receptors. We suggest that this motif is masked in full-length Y(1) receptors which do not constitutively internalize in the absence of agonist

Probabilistic partitioning methods to find significant patterns in ChIP-Seq data

Motivation: We have witnessed an enormous increase in ChIP-Seq data for histone modifications in the past few years. Discovering significant patterns in these data is an important problem for understanding biological mechanisms. Results: We propose probabilistic partitioning methods to discover significant patterns in ChIP-Seq data. Our methods take into account signal magnitude, shape, strand orientation and shifts. We compare our methods with some current methods and demonstrate significant improvements, especially with sparse data. Besides pattern discovery and classification, probabilistic partitioning can serve other purposes in ChIP-Seq data analysis. Specifically, we exemplify its merits in the context of peak finding and partitioning of nucleosome positioning patterns in human promoters