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Stage-specific control of early B cell development by the transcription factor Ikaros.

ABSTRACT: The transcription factor Ikaros is an essential regulator of lymphopoiesis. Here we studied its B cell-specific function by conditional inactivation of the gene encoding Ikaros (Ikzf1) in pro-B cells. B cell development was arrested at an aberrant 'pro-B cell' stage characterized by increased cell adhesion and loss of signaling via the pre-B cell signaling complex (pre-BCR). Ikaros activated genes encoding signal transducers of the pre-BCR and repressed genes involved in the downregulation of pre-BCR signaling and upregulation of the integrin signaling pathway. Unexpectedly, derepression of expression of the transcription factor Aiolos did not compensate for the loss of Ikaros in pro-B cells. Ikaros induced or suppressed active chromatin at regulatory elements of activated or repressed target genes. Notably, binding of Ikaros and expression of its target genes were dynamically regulated at distinct stages of early B lymphopoiesis.

SUBMITTER: Schwickert TA

PROVIDER: S-EPMC5790181 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Stage-specific control of early B cell development by the transcription factor Ikaros.

Schwickert Tanja A TA Tagoh Hiromi H Gültekin Sinan S Dakic Aleksandar A Axelsson Elin E Minnich Martina M Ebert Anja A Werner Barbara B Roth Mareike M Cimmino Luisa L Dickins Ross A RA Zuber Johannes J Jaritz Markus M Busslinger Meinrad M

Nature immunology 20140209 3

The transcription factor Ikaros is an essential regulator of lymphopoiesis. Here we studied its B cell-specific function by conditional inactivation of the gene encoding Ikaros (Ikzf1) in pro-B cells. B cell development was arrested at an aberrant 'pro-B cell' stage characterized by increased cell adhesion and loss of signaling via the pre-B cell signaling complex (pre-BCR). Ikaros activated genes encoding signal transducers of the pre-BCR and repressed genes involved in the downregulation of pr ...[more]

PMID: 24509509

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Project description:Transcription factors (TFs) regulate gene expression in living organisms. In higher organisms, TFs often interact in non-random combinations with each other to control gene transcription. Understanding the interactions is key to decipher mechanisms underlying tissue development. The aim of this study was to analyze co-occurring transcription factor binding sites (TFBSs) in a time series dataset from a new cell-culture model of human heart muscle development in order to identify common as well as specific co-occurring TFBS pairs in the promoter regions of regulated genes which can be essential to enhance cardiac tissue developmental processes. To this end, we separated available RNAseq dataset into five temporally defined groups: (i) mesoderm induction stage; (ii) early cardiac specification stage; (iii) late cardiac specification stage; (iv) early cardiac maturation stage; (v) late cardiac maturation stage, where each of these stages is characterized by unique differentially expressed genes (DEGs). To identify TFBS pairs for each stage, we applied the MatrixCatch algorithm, which is a successful method to deduce experimentally described TFBS pairs in the promoters of the DEGs. Although DEGs in each stage are distinct, our results show that the TFBS pair networks predicted by MatrixCatch for all stages are quite similar. Thus, we extend the results of MatrixCatch utilizing a Markov clustering algorithm (MCL) to perform network analysis. Using our extended approach, we are able to separate the TFBS pair networks in several clusters to highlight stage-specific co-occurences between TFBSs. Our approach has revealed clusters that are either common (NFAT or HMGIY clusters) or specific (SMAD or AP-1 clusters) for the individual stages. Several of these clusters are likely to play an important role during the cardiomyogenesis. Further, we have shown that the related TFs of TFBSs in the clusters indicate potential synergistic or antagonistic interactions to switch between different stages. Additionally, our results suggest that cardiomyogenesis follows the hourglass model which was already proven for Arabidopsis and some vertebrates. This investigation helps us to get a better understanding of how each stage of cardiomyogenesis is affected by different combination of TFs. Such knowledge may help to understand basic principles of stem cell differentiation into cardiomyocytes.

Project description:BACKGROUND: Aedes aegypti is the most important global vector of dengue virus infection in humans. Availability of the draft genome sequence of this mosquito provides unique opportunities to study different aspects of its biology, including identification of genes and pathways relevant to the developmental processes associated with transition across individual life stages. However, detailed knowledge of gene expression patterns pertaining to developmental stages of A. aegypti is largely lacking. RESULTS: We performed custom cDNA microarray analyses to examine the expression patterns among six developmental stages: early larvae, late larvae, early pupae, late pupae, and adult male and female mosquitoes. Results revealed 1,551 differentially expressed transcripts (DETs) showing significant differences in levels of expression between these life stages. The data suggests that most of the differential expression occurs in a stage specific manner in A. aegypti. Based on hierarchical clustering of expression levels, correlated expression patterns of DETs were also observed among developmental stages. Weighted gene correlation network analysis revealed modular patterns of expression among the DETs. We observed that hydrolase activity, membrane, integral to membrane, DNA binding, translation, ribosome, nucleoside-triphosphatase activity, structural constituent of ribosome, ribonucleoprotein complex and receptor activity were among the top ten ranked GO (Gene Ontology) terms associated with DETs. Significant associations of DETs were also observed with specific KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway modules. Finally, comparisons with the previously reported developmental transcriptome of the malaria vector, Anopheles gambiae, indicated that gene expression patterns during developmental processes reflect both species-specific as well as common components of the two mosquito species. CONCLUSIONS: Our study shows that genes involved in the developmental life cycle of A. aegypti are expressed in a highly stage-specific manner. This suggests that transcriptional events associated with transition through larval, pupal and adult stages are largely discrete.

Dataset Information

Stage-specific control of early B cell development by the transcription factor Ikaros.

Publications

Stage-specific control of early B cell development by the transcription factor Ikaros.

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