Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: Ikaros is an essential regulator of lymphopoiesis. Here, we studied the B-cell-specific function of Ikaros by conditional Ikzf1 inactivation in pro-B cells. B-cell development was arrested at an aberrant ‘pro-B’ cell stage characterized by increased cell adhesion and loss of pre-B cell receptor signaling. Ikaros was found to activate genes coding for pre-BCR signal transducers and to repress genes involved in the downregulation of pre-BCR signaling and upregulation of the integrin signaling pathway. Unexpectedly, derepression of Aiolos expression could not compensate for the loss of Ikaros in pro-B cells. Ikaros differentially controlled active chromatin at promoters and enhancers of repressed and activated target genes. Notably, Ikaros binding and target gene expression was dynamically regulated at distinct stages of early B-lymphopoiesis. 16 RNA-Seq samples in pre-proB cells (4 replicates, for each 2 controls and 2 experimental samples); 4 RNA-Seq samples in pro-B cells in Rag2-/- backgrounds (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in c-Kit high pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 2 RNA-Seq samples pre-B cells wild type; 8 chromatin ChIP-Seq samples (4x H3K9ac, 4x H3K4me3, Ikzf1 deleted/non deleted, two replicates each).; 4 Transcription factor ChIP-Seq samples in pro-B cells; 1 Transcription factor ChIP-Seq samples in DP-T cells; 1 Transcription factor ChIP-Seq samples in pre-pro-B cells; 2 Mi-2b Chip-Seq samples (Ikzf1 deleted versus non deleted); 1 ChIP-Seq input track for pro-B cells; 1 ChIP-Seq input track for DP-T cells

ORGANISM(S): Mus musculus

SUBMITTER: Markus Jaritz

PROVIDER: E-GEOD-53595 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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:The main goal of the project is to develop a new generation of bioinformatics resources for the integrative analysis of multiple types of 'omics data. These resources include both novel statistical methodologies as well as user-friendly software implementations. STATegra methods address many aspects of the 'omics data integration problem such as the design of multi-omics experiments, integrative transcriptional and regulatory networks, integrative variable selection, data fusion, integration of public domain data, and integrative pathway analysis. To support method development STATegra uses a model biological system, namely the differentiation process of mouse pre-B-cells. The STATegra consortium generated data focused on a critical step in the differentiation of B lymphocytes, which are key components of the adaptive immune system. Transcription factors of the Ikaros family are central to the normal differentiation of B cell progenitors and their expression increases in response to developmental stage-specific signals to terminate the proliferation of B cell progenitors and to initiate their differentiation. In particular, a novel biological system that models the transition from the pre-BI stage to the pre-BII subsequent stage, where B cell progenitors undergo growth arrest and differentiation, was used. The approach involves a pre-B cell line, B3, and an inducible version of the Ikaros transcription factor, Ikaros-ERt2. Ikaros factors act to down-regulate genes that drive proliferation and to simultaneously up-regulate the expression of genes that promote the differentiation of B cell progenitors. Hence, in the B3 system, before induction of Ikaros, cells proliferate and their gene expression pattern is similar to proliferating B cell progenitors in vivo. Following Ikaros induction, B3 cells undergo gene expression changes that resemble those that occur in vivo during the transition from cycling to resting pre-B cells, followed by a marked reduction in cellular proliferation and by G1 arrest. On this system the consortium has created a high-quality data collection consisting of a replicated time course using seven different 'omics platforms: RNA-seq, miRNA-seq, ChIP-seq, DNase-seq, Methyl-seq, proteomics and metabolomics, which is used to assess and to validate STATegra methods. The STATegra experimental design consists of a 6 point time course that captures the differentiation of B3 cells containing Ikaros-ERt2 upon Ikaros induction within a 24 hr period. The process was sampled at 0, 2, 6, 12, 18, and 24 hrs respectively after Ikaros induction by Tamoxifen. As control, B3 cells transfected with an empty vector were treated and sampled in the same way as the inducible line. Eight different 'omic technologies were measured on this system: RNA-seq, miRNA-seq, DNase-seq, RRBS-seq, ChIP-seq, scRNA-seq, Proteomics and Metabolomics. Generally, three biological replicates were obtained per platform and were processed as independent batches. Metabolomics analysis was performed using 4 biological batches (7, 8, 9 and 10) and at times 0, 2, 6, 12, 18 and 24 hrs respectively. Each sample was analyzed using gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS).

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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