Structural mechanism ofLIN28Bnucleosome targeting by OCT4 for pluripotency

Abstract

SUMMARYPioneer transcription factors are essential for cell fate changes by targeting closed chromatin. OCT4 is a crucial pioneer factor that can induce cell reprogramming. However, the structural basis of how pioneer factors recognize thein vivonucleosomal DNA targets is unknown. Here, we determine the high-resolution structures of the nucleosome containing humanLIN28BDNA and its complexes with the OCT4 DNA binding region. Three OCT4s bind the pre-positioned nucleosome by recognizing non-canonical DNA motifs. Two use their POUS domains by forming extensive hydrogen bonds. The other uses the POUS-loop-POUHD region; POUHD serves as a wedge to unwrap ∼25 base pair DNA. Biochemical studies suggest that multiple OCT4s cooperatively open the H1-condensed nucleosome array containing theLIN28Bnucleosome. Our study suggests a mechanism whereby OCT4s target theLIN28Bnucleosome by forming multivalent interactions with nucleosomal motifs, unwrapping nucleosomal DNA, evicting H1, and cooperatively open closed chromatin to initiate cell reprogramming.