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

Nat Struct Mol Biol

Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Published: April 2024

AI Article Synopsis

  • Pioneer transcription factors, like PU.1 and C/EBPα, play a key role in changing cell types by regulating hematopoietic stem cell differentiation.
  • The study reveals that PU.1 and C/EBPα work together to interact with nucleosomes, shifting DNA and unwrapping chromatin, which is crucial for gene accessibility.
  • A mutation in PU.1 linked to leukemia disrupts its ability to interact with nucleosomes, highlighting the importance of these interactions in maintaining normal cell function.

Article 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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Source
http://dx.doi.org/10.1038/s41594-023-01189-zDOI Listing

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