The spatial binding model of the pioneer factor Oct4 with its target genes during cell reprogramming

Li, Hanshuang; Ta, Na; Long, Chunshen; Zhang, Qiu-Tang; Li, Siyu; Liu, Shuai; Yang, Lei; Zuo, Yongchun

doi:10.1016/j.csbj.2019.09.002

Cited by 23 publications

(12 citation statements)

References 46 publications

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“…47 In future work, we will further analyze the effects of epigenetic disorders on reprogramming by integrating other multi-omics data, such as DNA methylation and histone modification data. 36,[48][49][50]…”

Section: Discussionmentioning

confidence: 99%

A Comparative Analysis of Single-Cell Transcriptome Identifies Reprogramming Driver Factors for Efficiency Improvement

Song

Yang

et al. 2020

Molecular Therapy - Nucleic Acids

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Terminally differentiated somatic cells can be reprogrammed into a totipotent state through somatic cell nuclear transfer (SCNT). The incomplete reprogramming is the major reason for developmental arrest of SCNT embryos at early stages. In our studies, we found that pathways for autophagy, endocytosis, and apoptosis were incompletely activated in nuclear transfer (NT) 2-cell arrest embryos, whereas extensively inhibited pathways for stem cell pluripotency maintenance, DNA repair, cell cycle, and autophagy may result in NT 4cell embryos arrest. As for NT normal embryos, a significant shift in expression of developmental transcription factors (TFs) Id1, Pou6f1, Cited1, and Zscan4c was observed. Compared with pluripotent gene Ascl2 being activated only in NT 2-cell, Nanog, Dppa2, and Sall4 had major expression waves in normal development of both NT 2-cell and 4-cell embryos. Additionally, Kdm4b/4d and Kdm5b had been confirmed as key markers in NT 2-cell and 4-cell embryos, respectively. Histone acetylases Kat8, Elp6, and Eid1 were co-activated in NT 2-cell and 4-cell embryos to facilitate normal development. Gadd45a as a key driver functions with Tet1 and Tet2 to improve the efficiency of NT reprogramming. Taken together, our findings provided an important theoretical basis for elucidating the potential molecular mechanisms and identified reprogramming driver factor to improve the efficiency of SCNT reprogramming.

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Section: Discussionmentioning

confidence: 99%

A Comparative Analysis of Single-Cell Transcriptome Identifies Reprogramming Driver Factors for Efficiency Improvement

Song

Yang

et al. 2020

Molecular Therapy - Nucleic Acids

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“…Hdac5 is a histone deacetylase involved in the regulation of early embryo development. Klf9 and Pou5f1 are key transcription factors that play important roles in early embryonic development ( Chen et al, 2016 ; Li et al, 2019 ). These genes were all hyper-methylated in SCNT embryos compared to in vivo fertilized embryos and showed highly specific differential methylation patterns.…”

Section: Resultsmentioning

confidence: 99%

Characterization of DNA Methylation Patterns and Mining of Epigenetic Markers During Genomic Reprogramming in SCNT Embryos

Cao

Zuo

et al. 2020

Front. Cell Dev. Biol.

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Somatic cell nuclear transfer (SCNT), also known as somatic cell cloning, is a commonly used technique to study epigenetic reprogramming. Although SCNT has the advantages of being safe and able to obtain pluripotent cells, early developmental arrest happens in most SCNT embryos. Overcoming epigenetic barriers is currently the primary strategy for improving reprogramming efficiency and improving developmental rate in SCNT embryos. In this study, we analyzed DNA methylation profiles of in vivo fertilized embryos and SCNT embryos with different developmental fates. Overall DNA methylation level was higher in SCNT embryos during global de-methylation process compared to in vivo fertilized embryos. In addition, promoter region, first intron and 3′UTR were found to be the major genomic regions that were hyper-methylated in SCNT embryos. Surprisingly, we found the length of re-methylated region was directly related to the change of methylation level. Furthermore, a number of genes including Dppa2 and Dppa4 which are important for early zygotic genome activation (ZGA) were not properly activated in SCNT embryos. This study comprehensively analyzed genome-wide DNA methylation patterns in SCNT embryos and provided candidate target genes for improving efficiency of genomic reprogramming in SCNT embryos. Since SCNT technology has been widely used in agricultural and pastoral production, protection of endangered animals, and therapeutic cloning, the findings of this study have significant importance for all these fields.

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“…It was discovered earlier that four TFs Oct4, Sox2, Klf4 and c-Myc (OSKM) could induce pluripotency in mouse and human fibroblasts [35]- [38]. Oct4 is a transcription factor necessary for embryogenesis of early pluripotency and maintenance of embryonic stem cell (ESC) function [39], [40]. In addition, HMs is also an important factor for the mechanism of cell fate transformation.…”

Section: A Dna Binding Profiles Of Oct4 and Hmsmentioning

confidence: 99%

Mining Key Regulators of Cell Reprogramming and Prediction Research Based on Deep Learning Neural Networks

Liu

et al. 2020

IEEE Access

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Deciphering the dynamic changes of core factors at different reprogramming stages plays an important role in elucidating the reprogramming mechanism of induced pluripotent stem cells (iPSCs) and improving their induction efficiency. The use of transcription factors (TFs) in combination with histone modification is vital to understand the multiple regulatory of pioneer factor. However, existing studies are not enough to consider the classification of stage-specific gene clusters from the perspective of multi-omic in the process of cell reprogramming. In this study, three stage-specific gene clusters of reprogramming initiation, maturation and stabilization phase were identified by using differential expression analysis. Considering the effects of regional binding preference, we further constructed a quantitative model on different genome regions (promoter, enhancer and enhancer subdivision region) by integrating the DNA binding profiles of Oct4 and three histone modifications (HMs). For promoter and enhancer regions, the receiver operating characteristic curve (Roc curve) of support vector machine (SVM) model was above 0.75 and predictive with the accuracy (Acc) about 66 ∼ 69%. But on enhancer subdivision region, the convolutional neural network (CNN) model we constructed showed more faithful predictive performance than the model on promoter and enhancer, which Roc curve area can reach 0.87. Taken together, our studies quantitatively reveal the cooperative effects of TFs and HMs on reprogramming stage-specific gene clusters, hoping to provide new sights in mining the key regulators of reprogramming.

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The spatial binding model of the pioneer factor Oct4 with its target genes during cell reprogramming

Cited by 23 publications

References 46 publications

A Comparative Analysis of Single-Cell Transcriptome Identifies Reprogramming Driver Factors for Efficiency Improvement

A Comparative Analysis of Single-Cell Transcriptome Identifies Reprogramming Driver Factors for Efficiency Improvement

Characterization of DNA Methylation Patterns and Mining of Epigenetic Markers During Genomic Reprogramming in SCNT Embryos

Mining Key Regulators of Cell Reprogramming and Prediction Research Based on Deep Learning Neural Networks

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