Throughout Metazoa, developmental processes are controlled by a surprisingly limited number of conserved signaling pathways. Precisely how these signaling cassettes were assembled in early animal evolution remains poorly understood, as do the molecular transitions that potentiated the acquisition of their myriad developmental functions. Here we analyze the molecular evolution of the proto-oncogene YAP/Yorkie, a key effector of the Hippo signaling pathway that controls organ size in both Drosophila and mammals. Based on heterologous functional analysis of evolutionarily distant Yap/Yorkie orthologs, we demonstrate that a structurally distinct interaction interface between Yap/Yorkie and its partner TEAD/Scalloped became fixed in the eumetazoan common ancestor. We then combine transcriptional profiling of tissues expressing phylogenetically diverse forms of Yap/Yorkie with ChIP-seq validation in order to identify a common downstream gene expression program underlying the control of tissue growth in Drosophila. Intriguingly, a subset of the newly-identified Yorkie target genes are also induced by Yap in mammalian tissues, thus revealing a conserved Yap-dependent gene expression signature likely to mediate organ size control throughout bilaterian animals. Combined, these experiments provide new mechanistic insights while revealing the ancient evolutionary history of Hippo signaling. We sought to define the downstream target genes of selected Yap variants by performing RNA sequencing analysis (RNA-seq) on total RNA isolated from GMR-Gal4>Yap eye discs. Overall design: Transcriptional profiles were generated in triplicate from eye imaginal disks with either endogenous Yki, or GMR-Gal4 over-expressed Yki, Trichoplax Yap, Monosiga Yap, or Monisiga Yap+TEAD domain, using deep sequencing via Illumina Hi Seq.
Molecular evolution of the Yap/Yorkie proto-oncogene and elucidation of its core transcriptional program.
Treatment, Subject
View SamplesArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown.
Myocardial transcriptome analysis of human arrhythmogenic right ventricular cardiomyopathy.
Sex, Age
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Poised RNA polymerase II changes over developmental time and prepares genes for future expression.
Specimen part, Cell line, Treatment, Time
View SamplesMurine ES cell gene expression before RA induction are used to compare gene expression for time-points of 8, 12, 16, 24, 36, 48, 60 and 72 hours post-induction.
Poised RNA polymerase II changes over developmental time and prepares genes for future expression.
Cell line, Treatment, Time
View SamplesPoised RNA polymerase II is predominantly found at developmental control genes and is thought to allow their rapid and synchronous induction in response to extracellular signals. How the recruitment of poised RNA Pol II is regulated during development is not known. By isolating muscle tissue from Drosophila embryos at five stages of differentiation, we show that the recruitment of poised Pol II occurs at many genes de novo and this makes them permissive for future gene expression. When compared to other tissues, these changes are stage-specific and not tissue-specific. In contrast, Polycomb group repression is tissue-specific and in combination with Pol II (the balanced state) marks genes with highly dynamic expression. This suggests that poised Pol II is temporally regulated and is held in check in a tissue-specific fashion. We compare our data to mammalian embryonic stem cells and discuss a framework for predicting developmental programs based on chromatin state. Overall design: mRNA-seq of Drosophila tissues during development
Poised RNA polymerase II changes over developmental time and prepares genes for future expression.
Specimen part, Subject, Time
View SamplesRNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptome of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2 under these conditions whereas retained RNA-binding capacity of TTP-AA to 3’UTRs caused profound changes in the transcriptome and translatome, altered NF-?B-activation and induced cell death. Increased TTP binding to the 3''UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-?B-signaling pathway. Taken together, our study uncovers a role for TTP in NF-?B-signaling and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control feedback signaling during the inflammatory response. Overall design: Comparison of the transcriptomes of TTP knockout macrophages inducibly expressing GFP, GFP-TTP or GFP-TTP-AA (S52A, S178A) phosphorylation mutant during 1h LPS stimulation. 3 biological replicates per genotype and condition.
The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
A comparative study of RNA-Seq and microarray data analysis on the two examples of rectal-cancer patients and Burkitt Lymphoma cells.
Cell line, Treatment
View SamplesRNA-Seq profiling of Burkitt Lymphoma cell line (BL2) with B-cell activating factor (BAFF) for 24 hrs . The Burkitt Lymphoma cell line were either only cultured in cell culture medium supplemented with 10 mM HEPES at 1 × 106 cells/ml or additionally incubated with B-cell activating factor (BAFF) for 24 hrs Overall design: Two conditions of BL2 cells each in 3 replicates: 1. non-stimulated control (BL2), 2. Baff stimulated (BL2Baff)
A comparative study of RNA-Seq and microarray data analysis on the two examples of rectal-cancer patients and Burkitt Lymphoma cells.
Treatment, Subject
View SamplesMicroarray profiling of Burkitt Lymphoma cell line (BL2) with B-cell activating factor (BAFF) for 24 hrs .
A comparative study of RNA-Seq and microarray data analysis on the two examples of rectal-cancer patients and Burkitt Lymphoma cells.
Cell line
View Samplesgene expression database and algorithm to define cell expression modules
Identifying gene expression modules that define human cell fates.
Specimen part
View Samples