Chromatin structure and dynamics

Division Of Basic Sciences - Nci

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Abstract

For FY22/23, we used cryo-EM to determine the structures of the nucleosomes containing native-DNA sequences bound to various pioneer transcription factors, including OCT4, Pu.1, FoxA1/GATA4, and Ascl1. Our studies provide structural insights into the hypothesis of pioneer transcription factors (PTF) by showing: (i) PTFs help evict H1 by direct blocking and by an allosteric effect; (ii) the DNA binding domain can serve as a wedge to unwrap the nucleosomal DNA; (iii) multiple PTFs can bind to the nucleosome, which may increase the overall residence time. In addition, we found surprisingly that PTFs may use non-canonical motifs instead of canonical motifs to bind the nucleosome. We also established a structural model of H1 bound to its chaperone TAF1-beta using NMR. We showed that TAF1-beta binds to the linker histone and functions as a chaperone by blocking H1 interactions with DNA.