microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

Guo, Xudong; Liu, Qidong; Wang, Guiying; Zhu, Shifeng; Gao, Lei; Hong, Wujun; Chen, Yafang; Wu, Minjuan; Liu, Houqi; Jiang, Cizhong

doi:10.1038/cr.2012.180

Cited by 89 publications

(78 citation statements)

References 45 publications

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“…The expression of endogenous miRNAs is regulated by transcription factors [160] . The expression of miR-29b is directly regulated by Sox2 during iPSC generation and miR-29b is an essential facilitator for Oct4, Klf4, Sox2, and c-Myc (or Oct4, Klf4, and Sox2) mediated reprogramming [161] . Reported reprogramming factors Oct4, Klf4, Sox2, and c-Myc have demonstrated that miRNAs play a crucial role in regulating stem cell fate events, such as reprogramming, differentiation, and self-renewal.…”

Section: Micrornas In Reprogrammingmentioning

confidence: 99%

MicroRNAs as novel regulators of stem cell fate

Choi

Hwang³

2013

WJSC

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Mounting evidence in stem cell biology has shown that microRNAs (miRNAs) play a crucial role in cell fate specification, including stem cell self-renewal, lineagespecific differentiation, and somatic cell reprogramming. These functions are tightly regulated by specific gene expression patterns that involve miRNAs and transcription factors. To maintain stem cell pluripotency, specific miRNAs suppress transcription factors that promote differentiation, whereas to initiate differentiation, lineagespecific miRNAs are upregulated via the inhibition of transcription factors that promote self-renewal. Small molecules can be used in a similar manner as natural miRNAs, and a number of natural and synthetic small molecules have been isolated and developed to regulate stem cell fate. Using miRNAs as novel regulators of stem cell fate will provide insight into stem cell biology and aid in understanding the molecular mechanisms and crosstalk between miRNAs and stem cells.Ultimately, advances in the regulation of stem cell fate will contribute to the development of effective medical therapies for tissue repair and regeneration. This review summarizes the current insights into stem cell fate determination by miRNAs with a focus on stem cell self-renewal, differentiation, and reprogramming. Small molecules that control stem cell fate are also highlighted.© 2013 Baishideng. All rights reserved. Key words:MicroRNA; Stem cell fate; Differentiation; Self-renewal; Reprogramming; Small molecule Core tip: Stem cells are important in regenerative medicine applications due to their capacity to self-renew and differentiate into specific cell types. MicroRNAs (miRNAs) are short non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Recent studies suggest that miRNAs are key molecules in the regulation of stem cell fate decisions; this regulation is manifested as the fine tuning of cell-and tissue-specific gene expression. This review summarizes the current insights into stem cell fate determination by miRNAs and focuses on stem cell self-renewal, differentiation, and reprogramming. Small molecules that control stem cell fate are also highlighted.

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Section: Micrornas In Reprogrammingmentioning

confidence: 99%

MicroRNAs as novel regulators of stem cell fate

Choi

Hwang³

2013

WJSC

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“…LincRNA-p21 was predominantly nuclear ( Figure 3A), consistent with a potential role in epigenetic regulation. Then, we employed RNA immunoprecipitation (RIP) with antibodies against a panel of chromatin modifiers detrimental for reprogramming [9][10][11][12]23] using lysates from MEFs reprogrammed with OSKM on day 12. Notably, there was a substantial enrichment for lincRNA-p21 in DNMT1 RIP and a less substantial enrichment in SETDB1 RIP, but no enrichment in DN-MT3A/B and SUV39H1 RIPs, relative to IgG control ( Figure 3B).…”

Section: Lincrna-p21 Associates With Setdb1 and Dnmt1 In Separate Repmentioning

confidence: 99%

The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters

et al. 2014

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Recent studies have boosted our understanding of long noncoding RNAs (lncRNAs) in numerous biological processes, but few have examined their roles in somatic cell reprogramming. Through expression profiling and functional screening, we have identified that the large intergenic noncoding RNA p21 (lincRNA-p21) impairs reprogramming. Notably, lincRNA-p21 is induced by p53 but does not promote apoptosis or cell senescence in reprogramming. Instead, lincRNA-p21 associates with the H3K9 methyltransferase SETDB1 and the maintenance DNA methyltransferase DNMT1, which is facilitated by the RNA-binding protein HNRNPK. Consequently, lincRNA-p21 prevents reprogramming by sustaining H3K9me3 and/or CpG methylation at pluripotency gene promoters. Our results provide insight into the role of lncRNAs in reprogramming and establish a novel link between p53 and heterochromatin regulation.

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“…19 The miR-29 family is also more broadly relevant to stem cell biology, as miR-29b recently was shown to be upregulated by Sox2 and required for reprogramming of fibroblasts into induced pluripotent stem cells. 20 Although little is known about how miR-29a transcript levels are regulated, CCAAT/enhancer-binding protein alpha (CEBPA) has been reported to positively regulate the miR-29a/b-1 cluster and expression of miR-29a/b is suppressed in acute myeloid leukemia (AML) patients with impaired CEBPA function. 21 To understand the physiologic role of miR-29a in normal hematopoietic development, we evaluated HSPCs in mice harboring a genetic deletion of the miR-29a/b-1 bicistron.…”

Section: Introductionmentioning

confidence: 99%

miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a

Dooley

Chung

et al. 2015

Blood

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• miR-29a maintains HSC function by targeting Dnmt3a.Hematopoietic stem cells (HSCs) possess the ability to generate all hematopoietic cell types and to self-renew over long periods, but the mechanisms that regulate their unique properties are incompletely understood. Herein, we show that homozygous deletion of the miR-29a/b-1 bicistron results in decreased numbers of hematopoietic stem and progenitor cells (HSPCs), decreased HSC self-renewal, and increased HSC cell cycling and apoptosis. The HSPC phenotype is specifically due to loss of miR-29a, because miR-29b expression is unaltered in miR-29a/b-1-null HSCs, and only ectopic expression of miR-29a restores HSPC function both in vitro and in vivo. HSCs lacking miR-29a/b-1 exhibit widespread transcriptional dysregulation and adopt gene expression patterns similar to normal committed progenitors. A number of predicted miR-29 target genes, including Dnmt3a, are significantly upregulated in miR-29a/b-1-null HSCs. The loss of negative regulation of Dnmt3a by miR-29a is a major contributor to the miR-29a/b-1-null HSPC phenotype, as both in vitro Dnmt3a short hairpin RNA knockdown assays and a genetic haploinsufficiency model of Dnmt3a restored the frequency and long-term reconstitution capacity of HSCs from miR-29a/b-1-deficient mice. Overall, these data demonstrate that miR-29a is critical for maintaining HSC function through its negative regulation of Dnmt3a. (Blood. 2015;125(14):2206-2216

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microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

Cited by 89 publications

References 45 publications

MicroRNAs as novel regulators of stem cell fate

MicroRNAs as novel regulators of stem cell fate

The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters

miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a

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