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      Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

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          Abstract

          Transcription factor (TF) proteins bind to DNA to regulate gene expression. Normally, accessibility to DNA is required for their function. However, in the nucleus, the DNA is often inaccessible, wrapped around histone proteins in nucleosomes forming the chromatin. Pioneer TFs are thought to induce chromatin opening by recognizing their DNA binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds to DNA in nucleosomes in a sequence-specific manner. Here, we reveal the structural dynamics of nucleosomes that mediate Oct4 binding from molecular dynamics simulations. Nucleosome flexibility and the amplitude of nucleosome motions such as breathing and twisting are enhanced in nucleosomes with multiple TF binding sites. Moreover, the regions around the binding sites display higher local structural flexibility. Probing different structures of Oct4-nucleosome complexes, we show that alternative configurations in which Oct4 recognizes partial binding sites display stable TF-DNA interactions similar to those observed in complexes with free DNA and compatible with the DNA curvature and DNA-histone interactions. Therefore, we propose a structural basis for nucleosome recognition by a pioneer TF that is essential for understanding how chromatin is unraveled during cell fate conversions.

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          Most cited references44

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          PARMBSC1: A REFINED FORCE-FIELD FOR DNA SIMULATIONS

          We present parmbsc1, a new force-field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (~140 μs) covering most of the DNA structural space. Parmbsc1 provides high quality results in diverse systems, solving problems of previous force-fields. Parmbsc1 aims to be a reference force-field for the study of DNA in the next decade. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.
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            The interaction landscape between transcription factors and the nucleosome

            Nucleosomes cover most of the genome and are thought to be displaced by transcription factors (TFs) in regions that direct gene expression. However, the modes of interaction between TFs and nucleosomal DNA remain largely unknown. Here, we have systematically explored interactions between the nucleosome and 220 TFs representing diverse structural families. Consistently with earlier observations, we find that the majority of the studied TFs have less access to nucleosomal DNA than to free DNA. The motifs recovered from TFs bound to nucleosomal and free DNA are generally similar; however, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many TFs preferentially bind close to the end of nucleosomal DNA, or to periodic positions at its solvent-exposed side. TFs often also bind to nucleosomal DNA in a particular orientation. Some TFs specifically interact with DNA located at the dyad position where only one DNA gyre is wound, whereas other TFs prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals striking differences in TF binding to free and nucleosomal DNA, and uncovers a rich interaction landscape between TFs and the nucleosome.
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              LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency.

              The RNA-binding proteins LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, but their exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can function effectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of both endogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In human fibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during the transition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28B facilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlighted roles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and in regulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds to mRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus, LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, and stem cell metabolism.
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                Author and article information

                Contributors
                Journal
                Biophys J
                Biophys J
                Biophysical Journal
                The Biophysical Society
                0006-3495
                1542-0086
                16 January 2020
                05 May 2020
                16 January 2020
                : 118
                : 9
                : 2280-2296
                Affiliations
                [1 ]In Silico Biomolecular Structure and Dynamics Group, Hubrecht Institute, Utrecht, the Netherlands
                [2 ]Department of Cellular and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
                [3 ]Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Münster, Germany; and
                [4 ]Medical Faculty, University of Münster, Münster, Germany
                Author notes
                []Corresponding author v.cojocaru@ 123456hubrecht.eu
                Article
                S0006-3495(20)30032-1
                10.1016/j.bpj.2019.12.038
                7202942
                32027821
                cf2d012e-4692-4e5e-b922-314dbc9843be
                © 2020 Biophysical Society.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 27 September 2019
                : 23 December 2019
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                Biophysics
                Biophysics

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