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Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

View Article: PubMed Central - PubMed

ABSTRACT

Background: The transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.

Results: To obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.

Conclusion: We have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

No MeSH data available.


Ets1-binding sites overlap with those of other B cell transcription factors. Venn diagrams to show overlap between Ets1-bound regions in primary mouse B cells with (A) Pax5-bound regions, (B) E2A-bound regions, and (C) Irf4-bound regions. Pax5, E2A, and Irf4 ChIP-seq data come from studies described in Ref. (51, 53, 54).
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Figure 2: Ets1-binding sites overlap with those of other B cell transcription factors. Venn diagrams to show overlap between Ets1-bound regions in primary mouse B cells with (A) Pax5-bound regions, (B) E2A-bound regions, and (C) Irf4-bound regions. Pax5, E2A, and Irf4 ChIP-seq data come from studies described in Ref. (51, 53, 54).

Mentions: ChIP-seq datasets are also available for Pax5 in mouse mature splenic B cells (51). We compared the binding sites of Pax5 with those bound by Ets1 to identify genes that might be co-regulated. There were 4,590 overlapping peaks common between Ets1 and Pax5 (Figure 2A), representing ~44% of all Ets1-bound regions and ~45% of all Pax5-bound regions. Among the genes having peaks for both Ets1 and Pax5 are some that encode genes that are crucial for B cell biology including CD79a, ICOS ligand, Foxp1, PLCĪ³2, and Vav1. Ontology enrichment analysis of the identified common targets of Ets1 and Pax5 indicate that they are associated with immune system activation and effector processes (not shown). This suggests that there is a strong overlap in function of Ets1 and Pax5 in B cells.


Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1
Ets1-binding sites overlap with those of other B cell transcription factors. Venn diagrams to show overlap between Ets1-bound regions in primary mouse B cells with (A) Pax5-bound regions, (B) E2A-bound regions, and (C) Irf4-bound regions. Pax5, E2A, and Irf4 ChIP-seq data come from studies described in Ref. (51, 53, 54).
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Related In: Results  -  Collection

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Figure 2: Ets1-binding sites overlap with those of other B cell transcription factors. Venn diagrams to show overlap between Ets1-bound regions in primary mouse B cells with (A) Pax5-bound regions, (B) E2A-bound regions, and (C) Irf4-bound regions. Pax5, E2A, and Irf4 ChIP-seq data come from studies described in Ref. (51, 53, 54).
Mentions: ChIP-seq datasets are also available for Pax5 in mouse mature splenic B cells (51). We compared the binding sites of Pax5 with those bound by Ets1 to identify genes that might be co-regulated. There were 4,590 overlapping peaks common between Ets1 and Pax5 (Figure 2A), representing ~44% of all Ets1-bound regions and ~45% of all Pax5-bound regions. Among the genes having peaks for both Ets1 and Pax5 are some that encode genes that are crucial for B cell biology including CD79a, ICOS ligand, Foxp1, PLCĪ³2, and Vav1. Ontology enrichment analysis of the identified common targets of Ets1 and Pax5 indicate that they are associated with immune system activation and effector processes (not shown). This suggests that there is a strong overlap in function of Ets1 and Pax5 in B cells.

View Article: PubMed Central - PubMed

ABSTRACT

Background: The transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.

Results: To obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.

Conclusion: We have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

No MeSH data available.