Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα

doi:10.1038/s41594-023-01189-z

. 2024 Apr;31(4):633-643.

doi: 10.1038/s41594-023-01189-z. Epub 2024 Jan 24.

Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα

Tengfei Lian^#¹, Ruifang Guan^#², Bing-Rui Zhou², Yawen Bai³

Affiliations

¹ Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tengfei.lian@nih.gov.
² Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³ Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. baiyaw@mail.nih.gov.

^# Contributed equally.

PMID: 38267599
DOI: 10.1038/s41594-023-01189-z

Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα

Tengfei Lian et al. Nat Struct Mol Biol. 2024 Apr.

. 2024 Apr;31(4):633-643.

doi: 10.1038/s41594-023-01189-z. Epub 2024 Jan 24.

Authors

Tengfei Lian^#¹, Ruifang Guan^#², Bing-Rui Zhou², Yawen Bai³

Affiliations

¹ Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tengfei.lian@nih.gov.
² Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³ Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. baiyaw@mail.nih.gov.

^# Contributed equally.

PMID: 38267599
DOI: 10.1038/s41594-023-01189-z

Abstract

Pioneer transcription factors are vital for cell fate changes. PU.1 and C/EBPα work together to regulate hematopoietic stem cell differentiation. However, how they recognize in vivo nucleosomal DNA targets remains elusive. Here we report the structures of the nucleosome containing the mouse genomic CX3CR1 enhancer DNA and its complexes with PU.1 alone and with both PU.1 and the C/EBPα DNA binding domain. Our structures reveal that PU.1 binds the DNA motif at the exit linker, shifting 17 bp of DNA into the core region through interactions with H2A, unwrapping ~20 bp of nucleosomal DNA. C/EBPα binding, aided by PU.1's repositioning, unwraps ~25 bp of entry DNA. The PU.1 Q218H mutation, linked to acute myeloid leukemia, disrupts PU.1-H2A interactions. PU.1 and C/EBPα jointly displace linker histone H1 and open the H1-condensed nucleosome array. Our study unveils how two pioneer factors can work cooperatively to open closed chromatin by altering DNA positioning in the nucleosome.

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Update of

Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα.
Lian T, Guan R, Zhou BR, Bai Y. Lian T, et al. bioRxiv [Preprint]. 2023 Aug 26:2023.08.25.554718. doi: 10.1101/2023.08.25.554718. bioRxiv. 2023. Update in: Nat Struct Mol Biol. 2024 Apr;31(4):633-643. doi: 10.1038/s41594-023-01189-z. PMID: 37790476 Free PMC article. Updated. Preprint.

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References

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[1] Larson, E. D., Marsh, A. J. & Harrison, M. M. Pioneering the developmental frontier. Mol. Cell 81, 1640–1650 (2021). - PubMed - PMC

[2] Larson, E. D., Marsh, A. J. & Harrison, M. M. Pioneering the developmental frontier. Mol. Cell 81, 1640–1650 (2021). - PubMed - PMC

[3] Balsalobre, A. & Drouin, J. Pioneer factors as master regulators of the epigenome and cell fate. Nat. Rev. Mol. Cell Biol. 23, 449–464 (2022). - PubMed

[4] Balsalobre, A. & Drouin, J. Pioneer factors as master regulators of the epigenome and cell fate. Nat. Rev. Mol. Cell Biol. 23, 449–464 (2022). - PubMed

[5] Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997). - PubMed

[6] Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997). - PubMed

[7] Zhou, B. R. et al. Distinct structures and dynamics of chromatosomes with different human linker histone isoforms. Mol. Cell 81, 166–182 e166 (2021). - PubMed

[8] Zhou, B. R. et al. Distinct structures and dynamics of chromatosomes with different human linker histone isoforms. Mol. Cell 81, 166–182 e166 (2021). - PubMed

[9] Zaret, K. S. Pioneer transcription factors initiating gene network changes. Annu. Rev. Genet. 54, 367–385 (2020). - PubMed - PMC

[10] Zaret, K. S. Pioneer transcription factors initiating gene network changes. Annu. Rev. Genet. 54, 367–385 (2020). - PubMed - PMC

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Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα

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Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα

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