Epigenetic reprogramming and induced pluripotency

Hochedlinger, Konrad; Plath, Kathrin

doi:10.1242/dev.020867

Cited by 505 publications

(394 citation statements)

References 167 publications

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“…These data indicate that Sox2-triggered miR-29b-DNMT signaling plays a crucial role in DNA methylation-related reprogramming events, including the regulation of MET and Dlk1-Dio3 transcription silencing. Genome-wide epigenetic remodeling is the determinant factor that leads to the distinct regulation of gene expression during cell reprogramming [43]. During iPSC generation, the defined factors Oct4 and Sox2 are crucial for regulating epigenetic remodeling events, including DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

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

Guo¹,

Liu

Wang

et al. 2012

Cell Res

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Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM-and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.

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Section: Discussionmentioning

confidence: 99%

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

Guo¹,

Liu

Wang

et al. 2012

Cell Res

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“…Many more initial binding events are distinct from the definitive binding pattern in embryonic stem (ES) cells or iPSCs that maintains pluripontency (Soufi et al 2012). Thus, the initial binding or scanning of the genome is quite promiscuous during reprogramming of somatic cells to pluripotency, and subsequent reorganization of the factors in the genome must occur to establish the final pluripotent state (Hochedlinger and Plath 2009). Of these factors, Oct3/4, Sox2, and Klf4 act as pioneer transcription factors in that they can access closed chromatin whether they bind together or alone ( Fig.…”

Section: Pioneer Factors In Cell Reprogrammingmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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“…The recent development of methods to reprogram somatic cells to induced pluripotent stem (iPS) cells using retroviral or lentiviral transduction of four genes (Oct3/4, Sox2, c-Myc, and Klf4) represents a major breakthrough in stem cell research [1][2][3]. Further analysis shows that three of these genes, Oct4, Sox2, and Klf4, are critical to the process and that c-Myc functions to enhance reprogramming efficiency [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Klf4 Interacts Directly with Oct4 and Sox2 to Promote Reprogramming

et al. 2009

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Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by ectopic expression of specific sets of transcription factors. Oct4, Sox2, and Klf4, factors that share many target genes in embryonic stem (ES) cells, are critical components in various reprogramming protocols. Nevertheless, it remains unclear whether these factors function together or separately in reprogramming. Here we show that Klf4 interacts directly with Oct4 and Sox2 when expressed at levels sufficient to induce iPS cells. Endogenous Klf4 also interacts with Oct4 and Sox2 in iPS cells and in mouse ES cells. The Klf4 C terminus, which contains three tandem zinc fingers, is critical for this interaction and is required for activation of the target gene Nanog. In addition, Klf4 and Oct4 co-occupy the Nanog promoter. A dominant negative mutant of Klf4 can compete with wild-type Klf4 to form defective Oct4/Sox2/ Klf4 complexes and strongly inhibit reprogramming. In the absence of Klf4 overexpression, interaction of endogenous Klf4 with Oct4/Sox2 is also required for reprogramming. This study supports the idea that direct interactions between Klf4, Oct4, and Sox2 are critical for somatic cell reprogramming.

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Epigenetic reprogramming and induced pluripotency

Cited by 505 publications

References 167 publications

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

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

Pioneer transcription factors in cell reprogramming

Klf4 Interacts Directly with Oct4 and Sox2 to Promote Reprogramming

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