Concurrent binding to DNA and RNA facilitates the pluripotency reprogramming activity of Sox2

Hou, Linlin; Wei, Yuanjie; Lin, Yingying; Wang, Xiwei; Lai, Yiwei; Yin, Meng; Chen, Yanpu; Guo, Xiangpeng; Wu, Senbin; Zhu, Yindi; Yuan, Jie; Tariq, Muhammad; Li, Na; Sun, Hao; Wang, Huating; Zhang, Xiaofei; Chen, Jiekai; Bao, Xichen; Jauch, Ralf

doi:10.1093/nar/gkaa067

Cited by 44 publications

(56 citation statements)

References 93 publications

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“…Based on the computational model, we predict that the interaction is mediated via the coiled-coil and SH2 domains of STAT3 and not through its DNA-binding domain, suggesting that NORAD does not compete with DNA for STAT3 binding (Figure S2D). In tune with this possibility, the SOX2 TF has been recently found to physically associate with DNA and RNA through distinct binding domains (Hou et al, 2020). Finally, we tested whether STAT3 affects the abundance of its target RNAs NORAD, SERF2, and MAD2L2.…”

Section: Resultsmentioning

confidence: 97%

“…These observations suggest that the coupling between transcription and post-transcriptional regulation may be mediated, among other mechanisms, by dual DNA-and RNA-binding proteins (DRBPs), proteins that evolved to bindDNA as well as RNA (Dvir et al, 2018;Hudson and Ortlund, 2014). Examples of such DRBPs are the pluripotency transcription factor (TF) SOX2 (Holmes et al, 2020;Hou et al, 2020) and the key regulator of chromatin architecture CTCF (Caudron-Herger et al, 2019;Kung et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the RNA-binding protein landscape in the pluripotency network of human embryonic stem cells

et al. 2021

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Embryonic stem cell (ESC) self-renewal and cell fate decisions are driven by a broad array of molecular signals. While transcriptional regulators have been extensively studied in human ESCs (hESCs), the extent to which RNA-binding proteins (RBPs) contribute to human pluripotency remains unclear. Here, we carry out a proteome-wide screen and identify 810 proteins that bind RNA in hESCs. We reveal that RBPs are preferentially expressed in hESCs and dynamically regulated during early stem cell differentiation. Notably, many RBPs are affected by knockdown of OCT4, a master regulator of pluripotency, several dozen of which are directly targeted by this factor. Using cross-linking and immunoprecipitation (CLIP-seq), we find that the pluripotency-associated STAT3 and OCT4 transcription factors interact with RNA in hESCs and confirm the binding of STAT3 to the conserved NORAD long-noncoding RNA. Our findings indicate that RBPs have a more widespread role in human pluripotency than previously appreciated.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Uncovering the RNA-binding protein landscape in the pluripotency network of human embryonic stem cells

et al. 2021

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“…A comparable number of bona-fide target factors (699 significantly modulated genes) was also identified by cDNA microarray in nasopharyngeal cancer cells [ 41 ]. This target spectrum is further expanded and diversified by interactions with RNA-based polynucleotides [ 42 , 43 , 44 ]. Accordingly, SOX2’s contributions to stemness are inherently multifactorial and are probably best described as an expression pattern shift.…”

Section: Molecular–functional Aspects Of Sox2-imposed Stemnessmentioning

confidence: 99%

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

Schaefer

Steiner

Lengerke

2020

IJMS

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Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular–functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.

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“…Furthermore, our results indicated that the Ubx-HD mediates a different binding affinity compared to the full-length protein. Sox2 also mediates RNA-binding via an additional 60 amino acid RNA-binding motif (RBM) (Hou et al, 2020). Even more important, the RBM domain of Sox2 provides RNA sequence specificity as shown by SELEX experiments.…”

Section: Discussionmentioning

confidence: 99%

The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II

Carnesecchi

Boumpas

et al. 2021

Preprint

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Transcription Factors (TFs) play a pivotal role in cell fate decision by coordinating distinct gene expression programs. Although most TFs act at the DNA regulatory layer, few TFs can bind RNA and modulate mRNA splicing. Yet, the mechanistic cues underlying TFs function in splicing remain elusive. Focusing on the Drosophila Hox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm and Drosophila cells indicate that Ubx regulates mRNA expression and splicing to promote distinct functions in defined cellular contexts. Ubx modulates splicing via its DNA-binding domain, the Homeodomain (HD). Our results demonstrate a new RNA-binding ability of Ubx in cells and in vitro. Notably, the N51 amino acid of the HD, which mediates Ubx-DNA interaction, is non-essential for Ubx-RNA interaction in vitro but is required in vivo. We find that the N51 amino acid is necessary to mediate interaction between Ubx and the active form of the RNA Polymerase II (Pol II S2Phos) in Drosophila cells. By combining molecular and imaging approaches, our results reveal that Ubx mediates elongation-coupled splicing via a dynamic interplay with active Pol II and chromatin binding. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity.

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Concurrent binding to DNA and RNA facilitates the pluripotency reprogramming activity of Sox2

Cited by 44 publications

References 93 publications

Uncovering the RNA-binding protein landscape in the pluripotency network of human embryonic stem cells

Uncovering the RNA-binding protein landscape in the pluripotency network of human embryonic stem cells

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II

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