Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Essential role of the Pax5 C-terminal domain in controlling B cell commitment and development

ABSTRACT: The B-cell regulator Pax5 consists of multiple domains, whose function we analyzed in vivo by deletion in Pax5. While B-lymphopoiesis was minimally affected in mice with homozygous deletion of the octapeptide or partial homeodomain, both sequences were required for optimal B-cell development. Deletion of the C-terminal regulatory domain 1 (CRD1) interfered with B-cell development, while elimination of CRD2 modestly affected B-lymphopoiesis. Deletion of CRD1 and CRD2 arrested B-cell development at an uncommitted pro-B cell stage. Most Pax5-regulated genes required CRD1 or both CRD1 and CRD2 for their activation or repression, as these domains induced or eliminated open chromatin at Pax5-activated or Pax5-repressed genes, respectively. Co-immunoprecipitation experiments demonstrated that the activating function of CRD1 is mediated through interaction with the chromatin-remodeling BAF, H3K4-methylating Set1A-COMPASS and H4K16-acetylating NSL complexes, while its repressing function depends on recruitment of the Sin3-HDAC and MiDAC complexes. These data provide novel molecular insight into how different Pax5 domains regulate gene expression to promote B-cell commitment and development.

ORGANISM(S): Mus musculus

PROVIDER: GSE224793 | GEO | 2023/08/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Essential role of the Pax5 C-terminal domain in controlling B cell commitment and development

Project description:Pax5 controls B-cell commitment, development and immunity by repressing B-lineage-inappropriate genes and activating B-cell-specific genes. In addition to the N-terminal DNA-binding paired domain, Pax5 contains a conserved octapeptide, partial homeodomain and C-terminal sequences with transactivating and inhibitory potential. To understand how the C-terminal domains of Pax5 contribute to the repression and activation function of Pax5, we performed Pax5 pulldown combined with mass spectrometry to identify coactivator or corepressor complexes that bind to the C-terminal regions of Pax5.

2023-08-24 | PXD040424 | Pride

The B cell identity factor Pax5 regulates distinct transcriptional programs in early and late B lymphopoiesis

Project description:Pax5 controls the identity and development of B cells by repressing lineage-inappropriate genes and activating B-cell-specific genes. Here, we used genome-wide approaches to identify Pax5 target genes in pro-B and mature B cells. In these cell types, Pax5 bound to 40% of the cis- regulatory elements defined by mapping Dnase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8,000 target genes, it regulated only 4% of them in pro-B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5-regulated genes in pro-B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro-B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro-B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B cell identity and function by regulating distinct target genes in early and late B lymphopoiesis. 44 samples (16 RNA-seq, 15 ChIP-seq, 6 DHS-seq, 5 Bio-ChIP-seq, 2 CAGE-seq). All but four samples in in 2 biological replicates (8819, 8275, 8095, 8666). WT and experimental samples are provided.

2012-06-14 | E-GEOD-38046 | biostudies-arrayexpress

The B cell identity factor Pax5 regulates distinct transcriptional programs in early and late B lymphopoiesis

2012-06-14 | GSE38046 | GEO

A comprehensive Proteomic Investigation of Ebf1 Heterozygosity in pro-B lymphocytes utilizing Data Independent Acquisition

Project description:Early B cell factor 1 (EBF1) is one of the key transcription factors required for orchestrating B-cell lineage development. Although studies have shown that Ebf1 haploinsufficiency is involved in the development of leukemia, no study has been conducted that characterizes the global effect of Ebf1 heterozygosity on the proteome of pro-B lymphocytes. Here, we employ both DIA (Data Independent Acquisition) and shotgun DDA (Data Dependent Acquisition) workflows for profiling proteins that are differently expressed between Ebf1+/+ and Ebf1+/- cells. Both DDA and DIA were able to reveal the downregulation of the EBF1 transcription factor in Ebf1+/- pro-B lymphocytes. Further examination of differentially expressed proteins by DIA revealed that, similar to EBF1, the expression of other B-cell lineage regulators, such as TCF3 and Pax5, is also down-regulated in Ebf1 heterozygous cells. Functional DIA analysis of differentially expressed proteins showed that EBF1 heterozygosity resulted in the deregulation of at least 8 transcription factors involved in lymphopoiesis, and to the deregulation of key proteins playing crucial roles in survival, development and differentiation of pro-B lymphocytes.

2017-12-20 | PXD008396 | Pride

Histone H3K4 methylation-dependent and independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation

Project description:Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed. Here, we generated ESCs harboring the deletion of the SET domain of Set1A (Set1AΔSET); surprisingly, the Set1A SET domain is dispensable for ESC proliferation and self-renewal. The removal of the Set1A SET domain does not diminish bulk H3K4 methylation in ESCs; instead, only a subset of genomic loci exhibited reduction in H3K4me3 in Set1AΔSET cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1AΔSET ESCs are unable to undergo normal differentiation, indicating the importance of Set1A-dependent H3K4 methylation during differentiation. Our data also indicate that during differentiation, Set1A but not Mll2 functions as the H3K4 methylase on bivalent genes and is required for their expression, supporting a model for transcriptional switch between Mll2 and Set1A during the self-renewing-to-differentiation transition. Together, our study implicates a critical role for Set1A catalytic methyltransferase activity in regulating ESC differentiation but not self-renewal and suggests the existence of context-specific H3K4 methylation that regulates transcriptional outputs during ESC pluripotency.

2017-09-26 | GSE98988 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2 and H3K9ac

Project description:STAT5 and IL-7 signaling are thought to control B-lymphopoiesis by regulating key transcription factor genes and activating VH gene segments at the Igh locus. Using conditional mutagenesis, we demonstrate that transgenic Bcl2 expression rescued the development of Stat5-deleted pro-B cells by compensating for the loss of Mcl-1. Ebf1 and Pax5 expression as well as VH recombination were normal in Bcl2-rescued pro-B cells lacking STAT5 or IL-7Ra. In agreement with this finding, STAT5-expressing pro-B cells contained little or no active chromatin at most VH genes. In contrast, Igk rearrangements were increased in STAT5- or IL-7Ra-deficient pro-B cells, consistent with direct binding of STAT5 to the intronic iEk enhancer in wild-type pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and suppress premature Igk recombination in early B-lymphopoiesis. comparison of wt vs Rag2-/- pro-B cells

2010-07-28 | E-GEOD-18278 | biostudies-arrayexpress

NIA15k screen. Pax5 +/+, Pax5 -/-, and Rag1-/- pro B cell lines.

Project description:The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression, while simultaneously activating the B cell gene expression program. We have performed a global gene expression screen of wild type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B-lymphopoiesis. We have also included Rag1-/- and wild type (+/+) proB cells starved of the cytokine IL-7 for 4 hours as controls. Rag1-/- proB cells are incapable of further differentiation due to an absence of immunoglobulin recombination and IL-7 is the major cytokine regulating proB cell growth. Keywords: comparison of genetically modified cell-lines

2007-10-26 | GSE9345 | GEO

The interdependency between MiDAC complex and MLL3/4 complexes

Project description:Enhancers play a pivotal role in gene transcriptional regulation in response to developmental cues. Active enhancers are marked by H3K4me1/2 and H3K27ac, while poised enhancers are marked by H3K27me3 instead of H3K27ac in addition to H3K4me1/2. How these histone modifications and/or other histone modification(s) at enhancers are regulated remains not fully understood. Through immunoprecipitation followed by mass spectrometry of UTX, a specific subunit of the enhancer associated COMPASS complex: MLL3/4, we identified DNTTIP1 and ELMSAN1, which are scaffolds of the mitotic deacetylase complex (MiDAC), as new UTX interactors. Our biochemistry data shows that UTX-ELMSAN1 is the interface between MiDAC and MLL3/4 complexes. The loss of MiDAC causes genome wide increase of H4K20ac, suggesting H4K20ac is a MiDAC substrate in vivo. H4K20ac is genome-wide co-localized with H3K4me1/2, H3K27ac, UTX, and MLL4, suggesting it is located at active enhancers. Genome-wide increased occupancy of UTX and MLL4 is observed at Dnttip1 knockout mES cells, which means under normal conditions MiDAC may repress MLL3/4-UTX’s genomic localization. However, we observe an increase of H3K4me2 but not H3K4me1 at those UTX & MLL4 increased loci. In MLL3/4 double knockout mES cells, Dnttip1 is reduced genome-wide, which however does not lead to a genome-wide increase of H4K20ac, but a genome-wide loss of it. At either H4K20ac or Dnttip1 reduction loci, we observe an increase of H3K27me3, suggesting the formation of repressed chromatin state which may suppress the increase of H4K20ac at Dnttip1 reduced loci. Our study for the first time reveals the functional intersection between MiDAC and MLL3/4 complexes.

2022-06-27 | GSE190323 | GEO

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [ChIP-Seq]

Project description:Cell type diversity during neuro-ectodermal (NE) differentiation is achieved through selective activation and silencing of neurodevelopmental genes. Here, we show a key role for the histone deacetylase complex MiDAC during neuronal differentiation of mouse embryonic stem cells (mESCs) into NE. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC mediates the removal of H4K20ac on the promoters and enhancers of pro-neural genes such as the axon guidance ligands Slit3 and Ntn1 while in parallel reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis thereby upregulating and inhibiting gene expression, respectively. Furthermore, neurite outgrowth defects in MiDAC KO neurons can be rescued by restoring Slit3/Robo3-Ntn1/Unc5b signaling. Taken together, our work suggests a crucial role for MiDAC in regulating the secretome of the Slit3/Robo3-Ntn1/Unc5b signaling axes to ensure the proper integrity of neurite development.

2020-04-08 | GSE131061 | GEO

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [RNA-Seq]

2020-04-08 | GSE131060 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data