NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment

Reynolds, Nicola; Latos, Paulina A.; Hynes-Allen, Antony; Loos, Remco; Leaford, Donna; O’Shaughnessy, Aoife; Mosaku, Olukunbi; Signolet, Jason; Brennecke, Philip; Kalkan, Tuezer; Costello, Ita; Humphreys, Peter; Mansfield, William; Nakagawa, Kentaro; Strouboulis, John; Behrens, Axel; Bertone, Paul; Hendrich, Brian

doi:10.1016/j.stem.2012.02.020

Cited by 207 publications

(246 citation statements)

References 48 publications

(57 reference statements)

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“…Thus, depletion of Mbd3/ NuRD upregulates the expression of key iPSC promoting factors, facilitating the generation of pluripotent cells. Apparently, modulatory activity of NuRD constrains differentiation of ESCs thereby directly controlling their immediate differentiation potential [14][15][16]19]. Depletion of other core components of the NuRD complex, such as Mbd2 or Mi2/CHD4, improved iPSC generation to the same extent as knockdown of Mbd3 (unpublished results).…”

Section: Discussionmentioning

confidence: 91%

“…2H). The observation that downregulation of Mbd3 can substitute for c-Myc or Sox2 in in iPSC generation (Oct4-GFP þ colonies) highlights the essential role of Mbd3 in controlling somatic cell reprogramming and cell fate decision [14,19]. Of note, reprogramming did not occur with Klf4 and c-Myc alone, indicating that depletion of Mbd3/NuRD does not replace Oct4 in iPSC formation.…”

Section: Depletion Of Mbd3 Facilitates Reprogramming In the Absence Omentioning

confidence: 98%

“…NuRD represses transcription by binding to methylated DNA, mediating heterochromatin formation, and transcriptional silencing [12,13]. Moreover, Mbd3/NuRD directly regulates expression of pluripotency genes in ESCs to modulate transcriptional heterogeneity and maintain ESC lineage commitment [14]. ESCs lacking Mbd3/NuRD retain Oct4 expression in the absence of the cytokine leukemia inhibitory factor (LIF) and have a restricted potential to differentiate [15,16], suggesting an important function of Mbd3/NuRD in the establishment or maintenance of pluripotency.…”

Section: Introductionmentioning

confidence: 99%

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NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

et al. 2013

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Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell-specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c-Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug-induced downregulation of Mbd3/ NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming.

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Section: Discussionmentioning

confidence: 91%

Section: Depletion Of Mbd3 Facilitates Reprogramming In the Absence Omentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

et al. 2013

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“…The differential expression patterns of some pluripotency regulators in different subpopulations have been linked to fine tuning the balance between self‐renewal and cell fate commitment 7, 14, 15, 16, 17. The mechanisms underlying gene expression heterogeneity in the pluripotent state are still not well understood, and evidence suggests that gene fluctuations could arise from stochastic noise in gene expression regulatory mechanisms 18, 19, 20, 21.…”

Section: Introductionmentioning

confidence: 99%

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Angarica

Sol

2016

BioEssays

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Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine.

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“…NuRD additionally has dynamic functions in regulating the balance between pluripotency and differentiation in mammalian embryonic stem cells (Hu & Wade 2012; Reynolds et al. 2012). …”

mentioning

confidence: 99%

The NuRD complex componentp66suppresses photoreceptor neuron regeneration in planarians

Vásquez-Doorman

Petersen

2016

Regeneration

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Regeneration involves precise control of cell fate to produce an appropriate complement of tissues formed within a blastema. Several chromatin‐modifying complexes have been identified as required for regeneration in planarians, but it is unclear whether this class of molecules uniformly promotes the production of differentiated cells. We identify a function for p66, encoding a DNA‐binding protein component of the NuRD (nucleosome remodeling and deacetylase) complex, as well as the chromodomain helicase chd4, in suppressing production of photoreceptor neurons (PRNs) in planarians. This suppressive effect appeared restricted to PRNs because p66 inhibition did not influence numbers of eye pigment cup cells (PCCs) and decreased numbers of brain neurons and epidermal progenitors. PRNs from p66(RNAi) animals differentiated with some abnormalities but nonetheless produced arrestin+ projections to the brain. p66 inhibition produced excess ovo+otxA+ PRN progenitors without affecting numbers of ovo+otxA− PCC progenitors, and ovo and otxA were each required for the p66(RNAi) excess PRN phenotype. Together these results suggest that p66 acts through the NuRD complex to suppress PRN production by limiting expression of lineage‐specific transcription factors.

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NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment

Cited by 207 publications

References 48 publications

NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

The NuRD complex componentp66suppresses photoreceptor neuron regeneration in planarians

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