Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex

Ragheb, Ramy; Gharbi, Sarah; Cramard, Julie; Ogundele, Oluwaseun; Kloet, Susan L.; Burgold, Thomas; Vermeulen, Michiel; Reynolds, Nicola; Hendrich, Brian

doi:10.1016/j.scr.2020.101867

Cited by 10 publications

(11 citation statements)

References 62 publications

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“…Here again, the Mbd3 mutant cells failed to properly induce the expression of lineage genes after 4 days (T, Sox17, Mixl1 and Eomes) whereas the downregulation of the pluripotency genes was not affected by the absence of Mbd3 (Fig 1D). These results are consistent with our previous results differentiating ES cells or primed human and mouse pluripotent cells lacking NuRD activity (14,22), and indicate that a fully functional . CC-BY-NC-ND 4.0 International license perpetuity.…”

Section: Mbd3/nurd Activity Is Required For Mouse Es Cells To Express...supporting

confidence: 93%

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells

Montibus

Ragheb

Diamanti

et al. 2023

Preprint

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As cells exit the pluripotent state and begin to commit to a specific lineage they must activate genes appropriate for that lineage while silencing genes associated with pluripotency and preventing activation of lineage-inappropriate genes. The Nucleosome Remodelling and Deacetylation (NuRD) complex is essential for pluripotent cells to successfully undergo lineage commitment. NuRD controls nucleosome density at regulatory sequences to facilitate transcriptional responses, and also has been shown to prevent unscheduled transcription (transcriptional noise) in undifferentiated pluripotent cells. How these activities combine to ensure cells engage a gene expression program suitable for successful lineage commitment has not been determined. Here we show that while NuRD is not required to silence all genes, its activity is important to restrict expression of genes primed for activation upon exit from the pluripotent state, and that NuRD activity facilitates their subsequent transcriptional activation. We further show that NuRD coordinates gene expression changes, which acts to maintain a barrier between different stable states. Thus NuRD-mediated chromatin remodelling serves multiple functions, including reducing transcriptional noise, priming genes for activation and coordinating the transcriptional response to facilitate lineage commitment.

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Section: Mbd3/nurd Activity Is Required For Mouse Es Cells To Express...supporting

confidence: 93%

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells

Montibus

Ragheb

Diamanti

et al. 2023

Preprint

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“…These studies suggest a predominantly suppressive role for NuRD in the regulation of gene expression. Whilst this is consistent with early models of NuRD activity as a repressive complex, more recent studies have presented a more nuanced role for NuRD in modulating gene expression, which may be neither activating or repressive, but acting to fine tune gene expression and reduce transcriptional noise (Bornelov et al, 2018; Burgold et al, 2019; Ragheb et al, 2020). Therefore, an important unanswered question is whether NuRD is primarily repressive in neuronal development, or whether it may facilitate control of active gene expression as demonstrated in stem cell models.…”

Section: Introductionsupporting

confidence: 81%

NuRD independent Mi-2 activity represses ectopic gene expression during neuronal maturation

Aughey

Forsberg

Grimes

et al. 2022

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During neuronal development, extensive changes to chromatin states occur to regulate lineage-specific gene expression. The molecular factors underlying the repression of non-neuronal genes in differentiated neurons are poorly characterised. The Mi2/NuRD complex is a multiprotein complex with nucleosome remodelling and histone deacetylase activity. Whilst NuRD has previously been implicated in the development of nervous system tissues the precise nature of the gene expression programmes that it coordinates are ill-defined. Furthermore, evidence from several species suggests that Mi-2 may be incorporated into multiple complexes that may not possess histone deacetylase activity. Here, we show that Mi-2 activity is required for suppressing the ectopic expression of germline genes in neurons independently of HDAC1/NuRD, whilst components of the NuRD complex including Mi-2 regulate neural gene expression to ensure proper development of the larval nervous system. We find that Mi-2 binding in the genome is dynamic during neuronal maturation and Mi-2 mediated repression of ectopic gene expression is restricted to the early stages of neuronal development, indicating that Mi-2/NuRD is required for establishing stable neuronal transcriptomes during the early stages of neuronal differentiation.

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“…Our experiments also show that assembly of the intact NuRD complex reduces the time NuRD-bound enhancers spend undergoing directed motion, and we propose that this may limit the re-organisation of enhancer-promoter interactions leading to more stable, long-lived interactions. This could explain the observed increase in transcriptional noise, or lowlevel inappropriate transcription, observed in both human and mouse ES cells lacking functional NuRD 68,69 .…”

Section: The Nurd Complex Modulates the Dynamics Of Enhancers To Control Transcriptionmentioning

confidence: 99%

Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics

Basu

Shukron²,

Ponjavic³

et al. 2020

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Enhancer-promoter dynamics are critical for the spatiotemporal control of gene expression, but it remains unclear how these dynamics are controlled by chromatin regulators, such as the nucleosome remodelling and deacetylase (NuRD) complex. Here, we use Hi-C experiments to show that the intact NuRD complex increases CTCF/Cohesin binding and the probability of the interaction of intermediate-range (~1Mb) genomic sequences.To understand how NuRD alters 3D genome structure in this way, we developed an approach to segment and extract key biophysical parameters from trajectories of the NuRD complex determined using live-cell 3D singlemolecule imaging. Unexpectedly, this revealed that the intact NuRD complex decompacts chromatin structure and makes NuRD-bound sequences move faster, thus increasing the overall volume of the nucleus that these sequences explore. Interestingly, we also uncovered a rare fast-diffusing state of chromatin that exhibits directed motion. The intact NuRD complex reduces the amount of time that enhancers/promoters remain in this fastdiffusing state, which we propose would otherwise re-organise enhancer-promoter proximity. Thus, we uncover an intimate connection between a chromatin remodeller and the spatial dynamics of the local region of the genome to which it binds.3D genome organisation is thought to be critical for the spatiotemporal control of gene expression. However, little is known about the multi-scale chromatin dynamics of cis-regulatory elements or how they relate to genome organisation. To probe these dynamics at the single-cell level, one of two complementary methods are typically used: either live-cell imaging 1-4 or single nucleus versions of chromosome conformation capture experiments (such as Hi-C), which reveal the proximity of DNA sequences in different individual fixed cells [5][6][7][8][9][10][11][12][13][14][15][16] . For example, live-cell tracking of enhancers and promoters has revealed fast diffusion (or 'stirring') during transcription 4 , but the mechanisms underlying these changes in enhancer dynamics or how they relate to Hi-C measurements of enhancer-promoter proximity remain unclear.The nucleosome remodelling and deacetylase (NuRD) complex is a highly conserved 1 MDa multisubunit protein complex that we have previously shown clusters in 3D space in the nucleus with active enhancers and promoters 16 . It combines two key enzymatic activities -nucleosome remodelling via its helicasecontaining ATPase (predominantly CHD4 in ES cells) and lysine deacetylation via its HDAC1/2 subunits [16][17][18][19][20][21][22] .These activities are thought to be present in two sub-complexes (Figure 1a). HDAC1/2 associates, along with the histone chaperones RBBP4/7, with the core scaffold proteins MTA1/2/3 (metastasis tumour antigens) to form a stable sub-complex with deacetylase activity 23 . The nucleosome remodeller CHD4 interacts with chromatin by itself and may also form a second sub-complex with GATAD2A/B and DOC1 (CDK2AP1) 23-25 .The methyl-CpG DNA binding domain proteins MBD2/3 ...

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Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex

Abstract: Graphical abstract

Cited by 10 publications

References 62 publications

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells

NuRD independent Mi-2 activity represses ectopic gene expression during neuronal maturation

Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics

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