20 research outputs found
Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells
Embryonic stem cells (ESC) have the potential to self-renew indefinitely and
to differentiate into any of the three germ layers. The molecular mechanisms
for self-renewal, maintenance of pluripotency and lineage specification are
poorly understood, but recent results point to a key role for epigenetic
mechanisms. In this study, we focus on quantifying the impact of histone 3
acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We
analyze genome-wide histone acetylation patterns and gene expression profiles
measured over the first five days of cell differentiation triggered by
silencing Nanog, a key transcription factor in ESC regulation. We explore the
temporal and spatial dynamics of histone acetylation data and its correlation
with gene expression using supervised and unsupervised statistical models. On a
genome-wide scale, changes in acetylation are significantly correlated to
changes in mRNA expression and, surprisingly, this coherence increases over
time. We quantify the predictive power of histone acetylation for gene
expression changes in a balanced cross-validation procedure. In an in-depth
study we focus on genes central to the regulatory network of Mouse ESC,
including those identified in a recent genome-wide RNAi screen and in the
PluriNet, a computationally derived stem cell signature. We find that compared
to the rest of the genome, ESC-specific genes show significantly more
acetylation signal and a much stronger decrease in acetylation over time, which
is often not reflected in an concordant expression change. These results shed
light on the complexity of the relationship between histone acetylation and
gene expression and are a step forward to dissect the multilayer regulatory
mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog
The FunGenES Database: A Genomics Resource for Mouse Embryonic Stem Cell Differentiation
Embryonic stem (ES) cells have high self-renewal capacity and the potential to differentiate into a large variety of cell types. To investigate gene networks operating in pluripotent ES cells and their derivatives, the “Functional Genomics in Embryonic Stem Cells” consortium (FunGenES) has analyzed the transcriptome of mouse ES cells in eleven diverse settings representing sixty-seven experimental conditions. To better illustrate gene expression profiles in mouse ES cells, we have organized the results in an interactive database with a number of features and tools. Specifically, we have generated clusters of transcripts that behave the same way under the entire spectrum of the sixty-seven experimental conditions; we have assembled genes in groups according to their time of expression during successive days of ES cell differentiation; we have included expression profiles of specific gene classes such as transcription regulatory factors and Expressed Sequence Tags; transcripts have been arranged in “Expression Waves” and juxtaposed to genes with opposite or complementary expression patterns; we have designed search engines to display the expression profile of any transcript during ES cell differentiation; gene expression data have been organized in animated graphs of KEGG signaling and metabolic pathways; and finally, we have incorporated advanced functional annotations for individual genes or gene clusters of interest and links to microarray and genomic resources. The FunGenES database provides a comprehensive resource for studies into the biology of ES cells
SUMOylation Represses Nanog Expression via Modulating Transcription Factors Oct4 and Sox2
Nanog is a pivotal transcription factor in embryonic stem (ES) cells and is essential for maintaining the pluripotency and self-renewal of ES cells. SUMOylation has been proved to regulate several stem cell markers' function, such as Oct4 and Sox2. Nanog is strictly regulated by Oct4/Sox2 heterodimer. However, the direct effects of SUMOylation on Nanog expression remain unclear. In this study, we reported that SUMOylation repressed Nanog expression. Depletion of Sumo1 or its conjugating enzyme Ubc9 increased the expression of Nanog, while high SUMOylation reduced its expression. Interestingly, we found that SUMOylation of Oct4 and Sox2 regulated Nanog in an opposing manner. SUMOylation of Oct4 enhanced Nanog expression, while SUMOylated Sox2 inhibited its expression. Moreover, SUMOylation of Oct4 by Pias2 or Sox2 by Pias3 impaired the interaction between Oct4 and Sox2. Taken together, these results indicate that SUMOylation has a negative effect on Nanog expression and provides new insights into the mechanism of SUMO modification involved in ES cells regulation
The pluripotent genome in three dimensions is shaped around pluripotency factors
It is becoming increasingly clear that the shape of the genome importantly influences transcription regulation. Pluripotent stem cells such as embryonic stem cells were recently shown to organize their chromosomes into topological domains that are largely invariant between cell types. Here we combine chromatin conformation capture technologies with chromatin factor binding data to demonstrate that inactive chromatin is unusually disorganized in pluripotent stem-cell nuclei. We show that gene promoters engage in contacts between topological domains in a largely tissue-independent manner, whereas enhancers have a more tissue-restricted interaction profile. Notably, genomic clusters of pluripotency factor binding sites find each other very efficiently, in a manner that is strictly pluripotent-stem-cell-specific, dependent on the presence of Oct4 and Nanog protein and inducible after artificial recruitment of Nanog to a selected chromosomal site. We conclude that pluripotent stem cells have a unique higher-order genome structure shaped by pluripotency factors. We speculate that this interactome enhances the robustness of the pluripotent state
Funerary Pithoi in Bronze Age Crete: Their Introduction and Significance at the Threshold of Minoan Palatial Society
Toward the end of the third millennium B.C.E., Minoan funerary customs changed, and people began to favor the use of clay receptacles-pithoi or larnakes-for the bodies of the dead. This article offers a comprehensive study of the funerary pithoi of the period, comprising a review of the available material and its classification, distribution, and dating, the relation of container to tomb types, and the specific use of pithoi within funerary ritual. It also assesses the importance of pithoi as an investment in terms of the material wealth that they represent and the knowledge of the complex techniques of handling dead bodies that they require. Finally, it examines the symbolic connotations of the pithos and argues that its wide adoption was part of a general turn toward the concept of the regeneration of life. This concept shifted the emphasis of the funerary realm toward the social dimension-namely, toward the reallocation of the roles and resources of the dead among the living. Such a shift helped people come to terms with contemporary social reality and shaped the agency of emerging elites, which led to the establishment of the first Minoan palaces and transformed Crete from a series of kin-based communities to a group of proto-states