Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes.
While most transcription factors exit the chromatin during mitosis and the genome becomes silent, a subset of factors remains and "bookmarks" genes for rapid reactivation as cells progress through the cell cycle. However, it is unknown whether such bookmarking factors bind to chromatin similarly in mitosis and how different binding capacities among them relate to function. We compared a diverse set of transcription factors involved in liver differentiation and found markedly different extents of mitotic chromosome binding. Among them, the pioneer factor FoxA1 exhibits the greatest extent of mitotic chromosome binding. Genomically, ~15% of the FoxA1 interphase target sites are bound in mitosis, including at genes that are important for liver differentiation. Biophysical, genome mapping, and mutagenesis studies of FoxA1 reveals two different modes of binding to mitotic chromatin. Specific binding in mitosis occurs at sites that continue to be bound from interphase. Nonspecific binding in mitosis occurs across the chromosome due to the intrinsic chromatin affinity of FoxA1. Both specific and nonspecific binding contribute to timely reactivation of target genes post-mitosis. These studies reveal an unexpected diversity in the mechanisms by which transcription factors help retain cell identity during mitosis.
Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Smilow Center for Translation Research, Philadelphia, PA 19104, USA.
Juan Manuel
JM
Caravaca
Greg
G
Donahue
Justin S
JS
Becker
Ximiao
X
He
Charles
C
Vinson
Kenneth S
KS
Zaret
D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D002875:Chromosomes / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008938:Mitosis; D008958:Models, Molecular; D009707:Nucleosomes; D011485:Protein Binding
D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009707:Nucleosomes