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Brg1 activates enhancer repertoires to establish B cell identity and modulate cell growth

ABSTRACT: Early B cell development is orchestrated by the combined activities of the transcriptional regulators E2A, EBF1, Foxo1 and Ikaros. However, how the genome-wide binding patterns of these regulators are modulated during B-lineage development remains to be determined. Here, we found that in lymphoid progenitors the chromatin remodeler Brg1 specified the B cell fate. In committed pro-B cells Brg1 regulated Igh locus contraction and controlled c-Myc expression to modulate the expression of genes that regulate ribosome biogenesis. In committed pro-B cells Brg1 also suppressed a pre-B lineage-specific pattern of gene expression. Finally, we found that Brg1 acted mechanistically to establish B cell fate and modulate cell growth by facilitating access of lineage-specific transcription factors to poised enhancer repertoires.

ORGANISM(S): Mus musculus

PROVIDER: GSE66978 | GEO | 2015/05/15

SECONDARY ACCESSION(S): PRJNA278629

REPOSITORIES: GEO

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Brg1 activates enhancer repertoires to establish B cell identity and modulate cell growth

Project description:Early B cell development is orchestrated by the combined activities of the transcriptional regulators E2A, EBF1, Foxo1 and Ikaros. However, how the genome-wide binding patterns of these regulators are modulated during B-lineage development remains to be determined. Here, we found that in lymphoid progenitors the chromatin remodeler Brg1 specified the B cell fate. In committed pro-B cells Brg1 regulated Igh locus contraction and controlled c-Myc expression to modulate the expression of genes that regulate ribosome biogenesis. In committed pro-B cells Brg1 also suppressed a pre-B lineage-specific pattern of gene expression. Finally, we found that Brg1 acted mechanistically to establish B cell fate and modulate cell growth by facilitating access of lineage-specific transcription factors to poised enhancer repertoires. 8 ATAC-Seq samples from sorted ALP and BLP (duplicates, control and Brg1-deleted), 4 ATAC-Seq samples from cultured pro-B cells (duplicates, control and Brg1-deleted), 2 Ikaros ChIP-seq samples (performed in Rag1-/- pro-B cells and in E2A-/- pre-pro-B cells), 1 Brg1 ChIP-seq sample and accompanying Input sample (both in Rag1-/- pro-B cells), 4 RNA-Seq samples from cultured pro-B cells (duplicates, control and Brg1-deleted), 6 RNA-Seq samples from cultured Rag1-/- pro-B cells (triplicates, control and Brg1-knock down).

2015-05-15 | E-GEOD-66978 | biostudies-arrayexpress

Establishment of Enhancer Repertoires that Orchestrate the Myeloid and Lymphoid Cell Fates (ChIP-Seq dataset)

2011-09-01 | GSE30858 | GEO

Establishment of Enhancer Repertoires that Orchestrate the Myeloid and Lymphoid Cell Fates (gene expression dataset 2)

2011-09-01 | GSE30856 | GEO

Establishment of Enhancer Repertoires that Orchestrate the Myeloid and Lymphoid Cell Fates (gene expression dataset 1)

2011-09-01 | GSE30855 | GEO

Multilineage Priming of Enhancer Repertoires Precedes Commitment to the B and Myeloid Cell Lineages in Hematopoietic Progenitors

2011-09-01 | GSE30859 | GEO

Establishment of Enhancer Repertoires that Orchestrate the Myeloid and Lymphoid Cell Fates (gene expression dataset 1)

Project description:Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by H3K4me1 in multipotent progenitors. However, H3K4me1 levels at a subset of enhancers are elevated during developmental progression, resulting in evolving enhancer repertoires that we propose orchestrate the myeloid and B cell fates. ChIP-Seq and gene expression profiling were performed in an inducible hematopoietic pluripotent cell line that can be differentiated into multiple lymphoid lineages. This submission contains gene expression profiling data. To characterize Id2-HPCs, we performed microarray analysis using RNA derived from cultured E2A-deficient cells, EBF-deficient cells and Id2-HPCs. Id2-HPC cells were cultured in IMDM medium supplemented with 10% FCS/2% PSG/β-me and IL7, Flt3-ligand, and SCF cytokines on S17 feeder cells in a humidified incubator at 37 degrees C with 5% CO2. Id2-HPC expanded cells were depleted of small (<1-5%) numbers of CD19-, CD25- and CD11b-positive cells by auto-MACS. E2A -/- and EBF -/- cells were cultured in IMDM supplemented with 10% FCS/2% PSG/β-me on S17 feeder cells in the presence of IL-7, Flt3-ligand, and SCF cytokines in a humidified incubator at 37 degree C with 5% CO2.

2011-08-31 | E-GEOD-30855 | biostudies-arrayexpress

Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

Project description:It is established that E2A and its antagonist, Id3, modulate developmental progression at the pre-TCR and TCR checkpoints. Here we show at a global scale how E2A promotes commitment to the T cell lineage and how pre-TCR mediated signalling affects E2A genome-wide occupancy. We find aberrant development of CD4 memory-like and TFH-like cells, T-B cell conjugates and, remarkably, B cell follicles in Id3-/-thymi. We also find that Id3-/-CD4 splenocytes exhibit increased numbers of TFH-like cells. We propose a model in which Id3 modulates the naive versus effector/memory cell fate. Collectively, these data show how E2A acts globally to orchestrate T-lineage development and that Id3 antagonizes E2A activity beyond the pre-TCR checkpoint to enforce the naive T cell fate. ChIP-Seq was performed in thymocytes isolated from either untreated Rag2-/-mice (DN3 cells) or Rag2-/- mice injected with anti-CD3e antibody (DN4 cells). ChIP used antibodies against either E2A or H3K4me1.

2011-07-31 | E-GEOD-30518 | biostudies-arrayexpress

Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

2011-07-31 | GSE30518 | GEO

A global network of transcription factors, involving E2A, EBF1 and FOXO1, that orchestrates the B cell fate

Project description:It is now established that the transcription factors E2A, EBF1 and FoxoM-BM- 1 play critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1 as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory codes. These associations were dynamic during developmental progression. Occupancy by the E2A isoform, E47, directly elevated the abundance as well as the pattern of histone H3K4 monomethylation across putative enhancer regions. Finally, the pro-B cell epigenome was divided into clusters of loci that show E2A, EBF and Foxo1 occupancy. From this analysis a global network consisting of transcriptional regulators, signaling and survival factors, was constructed that we propose orchestrates the B cell fate. ChIP-Seq and gene expression profiling was performed in a variety of genetically modified primary B cell populations and cell lines approximating developmental stages of B cell development.

2010-06-12 | E-GEOD-21978 | biostudies-arrayexpress

Chromatin remodelers and lineage specific factors interact to target enhancers to establish pro-neurosensory fate within otic ectoderm

Project description:Specification of Sox2+ pro-neurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce Sox2 expression and promote pro-neurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of Sox2 expression and lack of neurosensory identity, leading to abnormal apoptosis within the otic ectoderm. Brg1 binds to two of three distal 3' Sox2 enhancers occupied by Six1, and Brg1-binding to these regions depends on Eya1-Six1 activity. We demonstrate that the activity of these Sox2 enhancers in otic neurosensory cells specifically depends on binding to Six1. Furthermore, genome-wide and transcriptome profiling indicate that Brg1 may suppress apoptotic factor Map3k5 to inhibit apoptosis. Together, our findings reveal an essential role for Brg1, its downstream pathways, and their interactions with Six1/Eya1, in promoting pro-neurosensory fate induction in the otic ectoderm and subsequent neuronal lineage commitment and survival of otic cells.

2021-06-04 | GSE166588 | GEO

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