Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable Genomic Loci

• Published in: Molecular cell 2017-02, Vol.65 (4), p.589-603.e9
• Main Authors: Liu, Ziying, Kraus, W. Lee
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cell Line; chromatin; DNA; DNA - genetics; DNA - metabolism; embryonic stem cells; Embryonic Stem Cells - enzymology; Euchromatin - enzymology; Euchromatin - genetics; Gene Expression Regulation, Developmental; Genetic Loci; genome; Humans; loci; Mice; nucleosome; nucleosome rotational positioning; nucleosomes; Nucleosomes - enzymology; Nucleosomes - genetics; PARP-1; pioneer transcription factor; Pluripotent Stem Cells - enzymology; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Protein Binding; Signal Transduction; Sox2; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Time Factors; transcription; transcription (genetics); transcription factors; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.01.017

Pioneer transcription factors (TFs) function as genomic first responders, binding to inaccessible regions of chromatin to promote enhancer formation. The mechanism by which pioneer TFs gain access to chromatin remains an important unanswered question. Here we show that PARP-1, a nucleosome-binding protein, cooperates with intrinsic properties of the pioneer TF Sox2 to facilitate its binding to intractable genomic loci in embryonic stem cells. These actions of PARP-1 occur independently of its poly(ADP-ribosyl) transferase activity. PARP-1-dependent Sox2-binding sites reside in euchromatic regions of the genome with relatively high nucleosome occupancy and low co-occupancy by other transcription factors. PARP-1 stabilizes Sox2 binding to nucleosomes at suboptimal sites through cooperative interactions on DNA. Our results define intrinsic and extrinsic features that determine Sox2 pioneer activity. The conditional pioneer activity observed with Sox2 at a subset of binding sites may be a key feature of other pioneer TFs operating at intractable genomic loci. [Display omitted] •A subset of biologically important Sox2 genomic binding sites in mESCs requires PARP-1•PARP-1-dependent Sox2-binding sites reside in regions of intractable euchromatin•These Sox2 sites have a specific nucleosome rotational positioning of the Sox motif•PARP-1 stabilizes Sox2 binding through cooperative interactions on DNA Liu and Kraus show that PARP-1, a nucleosome-binding protein, facilitates the binding of the pioneer transcription factor Sox2 to intractable genomic loci in embryonic stem cells independently of PARP-1’s poly(ADP-ribosyl) transferase activity. PARP-1 is required in this context to maintain the expression of pluripotency genes and the stem cell phenotype.