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Cited by 30Genomics and Chromatin DynamicsT-cell and B-cell ImmunologyEpigenetics and DNA Methylation

EBF1 drives hallmark B cell gene expression by enabling the interaction of PAX5 with the MLL H3K4 methyltransferase complex

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Bullerwell, Charles E., Robichaud, Philippe Pierre, Deprez, Pierre M. L., Joy, Andrew P., Wajnberg, Gabriel, D’Souza, Darwin, Chacko, Simi, Fournier, Sébastien +4 more·2021·Scientific Reports
DOI 10.1038/s41598-021-81000-5PMC PMC7810865
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Abstract

PAX5 and EBF1 work synergistically to regulate genes that are involved in B lymphocyte differentiation. We used the KIS-1 diffuse large B cell lymphoma cell line, which is reported to have elevated levels of PAX5 expression, to investigate the mechanism of EBF1- and PAX5-regulated gene expression. We demonstrate the lack of expression of hallmark B cell genes, including CD19, CD79b, and EBF1, in the KIS-1 cell line. Upon restoration of EBF1 expression we observed activation of CD19, CD79b and other genes with critical roles in B cell differentiation. Mass spectrometry analyses of proteins co-immunoprecipitated with PAX5 in KIS-1 identified components of the MLL H3K4 methylation complex, which drives histone modifications associated with transcription activation. Immunoblotting showed a stronger association of this complex with PAX5 in the presence of EBF1. Silencing of KMT2A, the catalytic component of MLL, repressed the ability of exogenous EBF1 to activate transcription of both CD19 and CD79b in KIS-1 cells. We also find association of PAX5 with the MLL complex and decreased CD19 expression following silencing of KMT2A in other human B cell lines. These data support an important role for the MLL complex in PAX5-mediated transcription regulation.

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  • SCENIC+ analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, in agreement with literature.

    “This analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, and in agreement with literature15–20.”

    From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [16]

  • This approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers; Pax5 and Ebf1 for B cells; Tbx21 for T cells; Meis1, Maf and Gata4 for LSECs; Mef2c and Lhx2 for HSC; and Tead4, Sox9 and Hnf1b for BECs.

    “this approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers37; Pax5 and Ebf1 for B cells38; Tbx21 for T cells39; Meis1, Maf and Gata4 for LSECs40; Mef2c and Lhx2 for HSC41; and Tead4, Sox9 and Hnf1b for BECs42”

    From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [38]

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Cited by

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Authors
Bullerwell, C. E., Robichaud, P. P., Deprez, P. M. L., Joy, A. P., Wajnberg, G., D’Souza, D., Chacko, S., Fournier, S., Crapoulet, N., Barnett, D. A., Lewis, S. M., & Ouellette, R. J.
Affiliations
  • Atlantic Cancer Research Institute (CA)
  • Université de Moncton (CA)
Corresponding author
Ouellette, Rodney J.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-01-15
Volume
11
Issue
1
Pages
1537-1537
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-021-81000-5
PMC
PMC7810865
OpenAlex
W3122379329
Cited by
30
References
0
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 1
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research (14265)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
EBF1, PAX5, MLL complex, KMT2A, H3K4 methylation, B cell differentiation, CD19, CD79b, transcriptional regulation, diffuse large B-cell lymphoma, histone modifications
MeSH terms
B-Lymphocytes, Cell Differentiation, Gene Expression Regulation, Humans, Lymphocyte Activation, Methyltransferases, Trans-Activators, Gene Expression, Lymphoma, B-Cell, Antigens, CD19, Cell Lineage, Cell Line, Tumor, PAX5 Transcription Factor

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