C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment
Open accessAbstract
The PU.1 gene contains a 237-base pair distal enhancer located 14 kilobases upstream of its promoter. We have identified 2 sites within the PU.1 enhancer that strongly bind C/EBPalpha in a gel shift assay, and interaction with endogenous C/EBPalpha was confirmed by chromatin immunoprecipitation. Mutation of these DNA elements reduced activity of a distal enhancer-promoter construct 2- or 5-fold in a myeloid cell line, while mutation of a weaker C/EBPalpha-binding site located in the promoter minimally reduced activity in this context. These findings strengthen the link between C/EBPalpha and PU.1 expression. Reduction of C/EBPalpha activity in cases of acute myeloid leukemia may therefore contribute to transformation by reducing PU.1 levels. In addition, induction of PU.1 by C/EBPalpha during normal hematopoiesis may contribute to stem cell commitment to the myeloid lineages and further commitment to monopoiesis. Consistent with a requirement for C/EBPalpha induction of PU.1 during myeloid development, we demonstrate that C/EBPalpha induces monocytic development when expressed in PU.1(+/+), PU.1(+/-), or PU.1(+/kd) marrow myeloid progenitors but induces granulocyte lineage commitment in PU.1(kd/kd) cells lacking the PU.1 distal enhancer and does not induce either lineage in PU.1(-/-) cells.
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CEBPA binds to and induces Spi1 expression in HSPC.
“as CEBPA binds to and induces Spi1 expression in HSPC (Kummalue and Friedman, 2003; Yeamans et al., 2007).”
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C/EBP-α binds the promoter region of PU.1 and induces its transcription.
“As C/EBP-α binds the promoter region of PU.1 and induces its transcription30,31”
From MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway (2011) · cites this paper as [31]
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- Authors
- Yeamans, C., Wang, D., Paz-Priel, I., Torbett, B. E., Tenen, D. G., & Friedman, A. D.
- Affiliations
- Johns Hopkins University (US)
- Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD;
- Scripps Research Institute (US)
- Harvard University (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-11-01
- Volume
- 110
- Issue
- 9
- Pages
- 3136-3142
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2200910
- OpenAlex
- W2054342573
- Cited by
- 118
- References
- 9
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 2 · 2023: 8 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 4 · 2015: 13 · 2014: 1 · 2013: 9 · 2012: 6
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL082948, HL 082948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- C/EBPα, PU.1, distal enhancers, monopoiesis, myeloid lineage commitment, transcriptional activation, acute myeloid leukemia, hematopoiesis, granulopoiesis, transcription factor binding sites
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Binding Sites, Cell Differentiation, Cells, Cultured, Enhancer Elements, Genetic, Hematopoiesis, Humans, Mice, Transgenic, Models, Biological, Monocytes, Protein Binding, Proto-Oncogene Proteins, Trans-Activators, Cell Lineage, U937 Cells, CCAAT-Enhancer-Binding Protein-alpha, Mice
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