CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex
Weihan Liu,
Jeffrey L. Kurkewich,
Angela Stoddart,
Saira Khan,
Dhivyaa Anandan,
Alexandre N. Gaubil,
Donald J. Wolfgeher,
Lia Jueng,
Stephen J. Kron,
Megan E. McNerney
Affiliations
Weihan Liu
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA; Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA
Jeffrey L. Kurkewich
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Angela Stoddart
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Saira Khan
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Dhivyaa Anandan
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Alexandre N. Gaubil
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Donald J. Wolfgeher
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
Lia Jueng
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
Stephen J. Kron
The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA; Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA; Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
Megan E. McNerney
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA; The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA; Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics, Section of Hematology/Oncology, The University of Chicago, Chicago, IL 60637, USA; Corresponding author
Summary: CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
