OCT4 interprets and enhances nucleosome flexibility

MacCarthy, Caitlin M.; Huertas, Jan; Ortmeier, Claudia; Bruch, Hermann vom; Tan, Daisylyn Senna; D, Reinke; Sander, Astrid; Bergbrede, Tim; Jauch, Ralf; Schöler, Hans R.; Cojocaru, Vlad

doi:10.1093/nar/gkac755

Cited by 22 publications

(8 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, two recent cryo-EM structures of the pioneer transcription factor SOX2-nucleosome complexes showed different mechanisms of binding 21,22 . All this complicates the identification and characterization of human pioneer transcription factors pointing to the pressing need to develop predictors and classifiers 49,67–69 .…”

Section: Discussionmentioning

confidence: 99%

Detection of new pioneer transcription factors as cell-type specific nucleosome binders

Peng

Song

Teif

et al. 2023

Preprint

View full text Add to dashboard Cite

Wrapping of DNA into nucleosomes restricts DNA accessibility and the recognition of binding motifs by transcription factors. A certain class of transcription factors, so-called pioneer transcription factors, can specifically recognize their binding sites on nucleosomal DNA, initiate local chromatin opening and facilitate the binding of co-factors in a cell-type-specific manner. For the vast majority of human pioneer transcription factors, the locations of their binding sites, mechanisms of binding and regulation remain unknown. We have developed a computational method to predict the cell-type-specific ability of transcription factors to bind nucleosomes by integrating ChIP-seq, MNaseq-seq and DNase-seq data with the details of nucleosome structure. We have achieved classification accuracy with AUC=0.94 in discriminating pioneer factors from canonical transcription factors and predicted 32 potential pioneer transcription factors as nucleosome binders in embryonic cell differentiation. Lastly, we systemically analyzed the interaction modes between various pioneer factors and detected several clusters of distinctive binding sites on nucleosomal DNA.

show abstract

Section: Discussionmentioning

confidence: 99%

Detection of new pioneer transcription factors as cell-type specific nucleosome binders

Peng

Song

Teif

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…This has prompted speculations that Oct4 engages closed chromatin with just one of its domains 47 or even that POU S alone is involved in chromatin opening 51 . On the other hand, we showed that while Oct4 uses either the POU S and POU HD to recognize specific sequences on nucleosomes, the other domain scans unspecifically creating barriers to nucleosome closing 52 . The data presented here shows that removing POU HD abolishes both Oct4 DNA binding on SoxOct motifs (Fig.…”

Section: Resultsmentioning

confidence: 93%

Enhancing Sox/Oct cooperativity induces higher-grade developmental reset

MacCarthy

Malik

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The discovery of induced pluripotent stem cell (iPSC) technology by Shinya Yamanaka has truly enabled the stem cell field. After 16 years of intense research, the delivery methods and culture media have improved but the original factors − Oct4, Sox2, Klf4, and Myc (OSKM) − remain central for driving reprogramming. Here we define structural elements in chimeric Sox2/Sox17 transcription factors that rescued the ability of nonfunctional Oct factors to induce pluripotency. Most importantly, we discovered a single amino acid swap in the DNA-binding domain of Sox2, A61V, that stabilizes the Sox/Oct heterodimer on DNA through hydrophobic interaction with Oct. The highly cooperative Sox2AV mutant enables iPSC generation with Oct4 orthologs, such as Oct2 and Oct6, as well as rescues otherwise detrimental Oct4 mutants and domain deletions. Sox2AV has a dramatic effect on the cell fate reset, significantly improving the developmental potential of OSKM iPSCs. Moreover, by swapping multiple beneficial elements of Sox17 into Sox2 we have built a chimeric super-SOX factor − Sox2-17 − that delivers unprecedented reprogramming efficiency and kinetics in five tested species. Sox2-17 enhances five-, four-, and three-factor reprogramming up to hundreds of times, enables two-factor generation of human iPSCs, and allows integration-free reprogramming of otherwise non-permissive aged human, non-human primate, and cattle fibroblasts. Our study demonstrates that a complete developmental reset requires both robust activation of regulatory elements controlled by the canonical SoxOct motif and limiting cellular proliferation driven by Oct4 and Myc. A high level of Sox2 expression and Sox2/Oct4 heterodimerization emerge as the key determinants of high-grade pluripotency that fades along the naive-to-primed continuum. Transient expression of SK cocktail can restore the naivety, providing a powerful technology to induce more complete developmental reset in pluripotent cells across species.

show abstract

“…The atomic resolution provided clues that the amplitude of nucleosome motions such as breathing and twisting were increased by the binding of Oct4 to multiple TF binding sites with a higher local structural flexibility [ 108 ]. A detailed regulatory mechanism of nucleosome dynamics by TF was proposed by MacCarthy et al, who suggested that Oct4 altered the optimal wrapping of the two gyres around each other and the histones but did not mediate nucleosome opening [ 109 ]. It has been indicated that intrinsic nucleosome flexibility is important for Oct4 binding, and the magnitude of Oct4’s impact on nucleosome dynamics is dependent on the binding site position and the mobility of histone tails.…”

Section: Multiple Regulatory Factors and Associated Mechanismmentioning

confidence: 99%

Studies of the Mechanism of Nucleosome Dynamics: A Review on Multifactorial Regulation from Computational and Experimental Cases

2023

View full text Add to dashboard Cite

The nucleosome, which organizes the long coil of genomic DNA in a highly condensed, polymeric way, is thought to be the basic unit of chromosomal structure. As the most important protein–DNA complex, its structural and dynamic features have been successively revealed in recent years. However, its regulatory mechanism, which is modulated by multiple factors, still requires systemic discussion. This study summarizes the regulatory factors of the nucleosome’s dynamic features from the perspective of histone modification, DNA methylation, and the nucleosome-interacting factors (transcription factors and nucleosome-remodeling proteins and cations) and focuses on the research exploring the molecular mechanism through both computational and experimental approaches. The regulatory factors that affect the dynamic features of nucleosomes are also discussed in detail, such as unwrapping, wrapping, sliding, and stacking. Due to the complexity of the high-order topological structures of nucleosomes and the comprehensive effects of regulatory factors, the research on the functional modulation mechanism of nucleosomes has encountered great challenges. The integration of computational and experimental approaches, the construction of physical modes for nucleosomes, and the application of deep learning techniques will provide promising opportunities for further exploration.

show abstract

OCT4 interprets and enhances nucleosome flexibility

Cited by 22 publications

References 68 publications

Detection of new pioneer transcription factors as cell-type specific nucleosome binders

Detection of new pioneer transcription factors as cell-type specific nucleosome binders

Enhancing Sox/Oct cooperativity induces higher-grade developmental reset

Studies of the Mechanism of Nucleosome Dynamics: A Review on Multifactorial Regulation from Computational and Experimental Cases

Contact Info

Product

Resources

About