@article{fcefbe7c400040f69056942b8834d2bc,
title = "Structural Features of Transcription Factors Associating with Nucleosome Binding",
abstract = "Fate-changing transcription factors (TFs) scan chromatin to initiate new genetic programs during cell differentiation and reprogramming. Yet the protein structure domains that allow TFs to target nucleosomal DNA remain unexplored. We screened diverse TFs for binding to nucleosomes containing motif-enriched sequences targeted by pioneer factors in vivo. FOXA1, OCT4, ASCL1/E12α, PU1, CEBPα, and ZELDA display a range of nucleosome binding affinities that correlate with their cell reprogramming potential. We further screened 593 full-length human TFs on protein microarrays against different nucleosome sequences, followed by confirmation in solution, to distinguish among factors that bound nucleosomes, such as the neuronal AP-2α/β/γ, versus factors that only bound free DNA. Structural comparisons of DNA binding domains revealed that efficient nucleosome binders use short anchoring α helices to bind DNA, whereas weak nucleosome binders use unstructured regions and/or β sheets. Thus, specific modes of DNA interaction allow nucleosome scanning that confers pioneer activity to transcription factors.",
keywords = "Ascl1, FoxA, NHLH2, Pu.1, RBPJ, TFAP2A, nucleosome binding, pioneer transcription factor, protein microarray",
author = "{Fernandez Garcia}, Meilin and Moore, {Cedric D.} and Schulz, {Katharine N.} and Oscar Alberto and Greg Donague and Harrison, {Melissa M.} and Heng Zhu and Zaret, {Kenneth S.}",
note = "Funding Information: We thank Dr. Dario Nicetto and members of the Zaret lab for critical discussions and comments on the manuscript and Drs. Moritz Mall and Marius Wernig for sharing findings and discussions on neuronal TFs. The work was supported by NRSF F31 GM112417-02 to M.F.G. and NIH R37GM36477 to K.S.Z. Work in the Harrison lab was supported by NIH R01GM11694 and a Vallee Scholar Award. M.F.G. and K.S.Z. conceived the study and designed the experiments. M.F.G. carried out genomic data analysis, nucleosome reconstitution, EMSAs, DNase footprinting, and protein purifications with O.A. K.N.S. purified ZLD and consulted on ZLD-binding experiments. C.D.M. carried out protein microarray experiments and data analysis with M.F.G. and G.D.; M.F.G. and K.S.Z. supervised personnel, interpreted data, and wrote the manuscript; and M.M.H. C.D.M. and H.Z. provided comments to the manuscript. The authors declare no competing interests. Funding Information: We thank Dr. Dario Nicetto and members of the Zaret lab for critical discussions and comments on the manuscript and Drs. Moritz Mall and Marius Wernig for sharing findings and discussions on neuronal TFs. The work was supported by NRSF F31 GM112417-02 to M.F.G. and NIH R37GM36477 to K.S.Z. Work in the Harrison lab was supported by NIH R01GM11694 and a Vallee Scholar Award . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "5",
doi = "10.1016/j.molcel.2019.06.009",
language = "English (US)",
volume = "75",
pages = "921--932.e6",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}