Nucleosome binding by the pioneer transcription factor OCT4

Echigoya, Kenta; Koyama, Michihisa; Negishi, Lumi; Takizawa, Yoshimasa; Mizukami, Yuka; Shimabayashi, Hideki; Kuroda, Akari; Kurumizaka, Hitoshi

doi:10.1038/s41598-020-68850-1

Cited by 39 publications

(43 citation statements)

References 57 publications

(86 reference statements)

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“…It was found that 9 out of the 13 TFs are predicted to have end preference including OCT4/POU5F1 and p53. This result is consistent with previous studies that these two proteins interact with the end of nucleosomal DNA [ 30 , 31 ].…”

Section: Resultssupporting

confidence: 94%

Machine learning predicts nucleosome binding modes of transcription factors

Kishan

Subramanya

et al. 2021

BMC Bioinformatics

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Background Most transcription factors (TFs) compete with nucleosomes to gain access to their cognate binding sites. Recent studies have identified several TF-nucleosome interaction modes including end binding (EB), oriented binding, periodic binding, dyad binding, groove binding, and gyre spanning. However, there are substantial experimental challenges in measuring nucleosome binding modes for thousands of TFs in different species. Results We present a computational prediction of the binding modes based on TF protein sequences. With a nested cross-validation procedure, our model outperforms several fine-tuned off-the-shelf machine learning (ML) methods in the multi-label classification task. Our binary classifier for the EB mode performs better than these ML methods with the area under precision-recall curve achieving 75%. The end preference of most TFs is consistent with low nucleosome occupancy around their binding site in GM12878 cells. The nucleosome occupancy data is used as an alternative dataset to confirm the superiority of our EB classifier. Conclusions We develop the first ML-based approach for efficient and comprehensive analysis of nucleosome binding modes of TFs.

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Section: Resultssupporting

confidence: 94%

Machine learning predicts nucleosome binding modes of transcription factors

Kishan

Subramanya

et al. 2021

BMC Bioinformatics

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“…Furthermore, mutating each site individually revealed that each site contributes to Oct4's affinity for the LIN28B nucleosome except the Sox site and HD -1 sites (Figure 1C, right panel; Figure S1). It also showed that HD -7 is the primary Oct4 binding site in agreement with two recent studies that also reported Oct4 binding to the HD -7 site (16,18). The sites previously proposed by Soufi et al (10, 11) HD -4.5 and S -1.5 are secondary binding sites.…”

Section: Resultssupporting

confidence: 89%

“…The histone tails were not resolved in these structures. Recently, Echigoya et al resolved the structure of a genomic nucleosome bound by Oct4 in the absence of Oct4 and revealed an Oct4 binding site different that those described by Soufi et al (18). In addition, they showed that Oct4 interacts with the histone H3 and competes with the linker histone for binding.…”

Section: Introductionmentioning

confidence: 91%

“…Structural studies of pTFs often use synthetic sequences, which are proven to tightly bind the histone core in one location making them well-suited for structural techniques. Research on Oct4 pTF activity using either synthetic or native sequences all reported Oct4 utilizing only half of its eight base pair binding site due to the twist of DNA and a sterical clash with the histone core, which inhibits the canonical binding of the second subdomain (11,15,16,18).…”

Section: Introductionmentioning

confidence: 99%

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OCT4 interprets and enhances nucleosome flexibility

Huertas

Ortmeier

et al. 2021

Preprint

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Pioneer transcription factors induce cellular identity transitions by binding to sites on inaccessible DNA wrapped in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA sites. The structural basis of their interaction with the chromatin structural unit, the nucleosome, is still unresolved. From a combination of experiments and molecular simulations we reveal here how Oct4, the master regulator and inducer of cellular pluripotency, interprets and enhances nucleosome structural flexibility. The magnitude of Oct4 impact on nucleosome dynamics depends on the binding site position and the mobility of unstructured tails of nucleosomal histone proteins. Oct4 propagates and stabilizes open nucleosome conformations by specific sequence recognition and unspecific DNA exploration. Our findings provide a structural basis for the versatility of transcription factors in engaging with nucleosomes and have implications for understanding how pioneer factors induce chromatin dynamics.

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“…The promoters of eukaryotes contain various sites with different a nity for the binding of diverse transcription factors. Transcription factors bind to speci c DNA sequences in the promoter regions of genes to activate or repress transcription of multiple target genes (Echigoya et al 2020;Kim and O'Shea 2008). We performed additional detailed truncation analysis of the promoter region in HEK-293, U87, and SH-SY5Y cell lines.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Haplotypes and Promoter Activity at the 5’ Region of the ADH7 Gene

Zeng

Gao

et al. 2021

Preprint

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Background: The function of the 5’ regulatory region and the role of the different SNP loci have not been well characterized. This study investigated the effect of several ADH7 haplotypes on the regulation of gene expression in vitro and the functional sequences in the 5’ regulatory region of ADH7. Three SNPs (rs17537595, rs2851028, and rs2654847) and four different haplotypes (T-C-T, T-T-T, C-T-T, T-C-A) were identified by cloning and sequencing. Methods: Effects of 4 different haplotypes and 8 truncated fragments of 5’ regulatory region on ADH7 gene expression were detected using a dual-luciferase reporter assay system. All recombinant plasmids were transfected into HEK-293, U87, and SH-SY5Y cells, respectively, and their relative fluorescence intensity was measured.Results: In HEK-293, U87, and SH-SY5Y cell lines, the relative fluorescence intensity of haplotype T-C-T was significantly higher than that of haplotype T-T-T, C-T-T, and T-C-A. Additionally, we found that regions from -83 to -310bp (ATG, +1), -560 to -768bp , and -987bp to -1203bp up-regulated gene expression. In contrast, the region from -768 to -987bp down-regulated gene expression. The gene expression of regions from -1203 to -1369bp and -1369 to -1626bp was down-regulated in U87 and SH-SY5Y cell lines, but the trend was opposite in HEK-293 cell line. The region from -310 to -560bp up-regulated gene expression in SH-SY5Y cell line, but down-regulated gene expression in HEK-293 and U87 cell lines.Conclusions: This study has shown that the polymorphisms of ADH7 5’ regulatory region play an important role in the regulation of gene expression.

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Nucleosome binding by the pioneer transcription factor OCT4

Cited by 39 publications

References 57 publications

Machine learning predicts nucleosome binding modes of transcription factors

Machine learning predicts nucleosome binding modes of transcription factors

OCT4 interprets and enhances nucleosome flexibility

Functional Analysis of Haplotypes and Promoter Activity at the 5’ Region of the ADH7 Gene

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