Nono, a Bivalent Domain Factor, Regulates Erk Signaling and Mouse Embryonic Stem Cell Pluripotency

Ma, Chun; Karwacki-Neisius, Violetta; Tang, Haoran; Li, Wenjing; Shi, Zhennan; Hu, Hongzhi; Xu, Wenqi; Wang, Zhentian; Kong, Lingchun; Lv, Ruitu; Fan, Zheng; Zhou, Wenhao; Yang, Pengyuan; Wu, Feizhen; Diao, Jiang; Tan, Li; Shi, Yujiang Geno; Lan, Fei; Shi, Yang

doi:10.1016/j.celrep.2016.09.078

Cited by 43 publications

(60 citation statements)

References 49 publications

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“…Most genes repressed by Polycomb in ESCs are kept in a poised state through their association with an unusual form of RNAPII characterized by the S5p modification (Stock et al, 2007;Brookes et al, 2012;Tee et al, 2014;Ma et al, 2016). The PRC/S5p promoter state is thought to play an important role in the regulation of cell plasticity, conferring pluripotent stem cells with the ability to rapidly activate specific subgroups of genes in response to developmental stimuli (Brookes & Pombo, 2009;Voigt et al, 2012;Di Croce & Helin, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Poised RNAPII‐S5p, in the absence of 8WG16, has not been described in Drosophila (Gaertner et al , ), consistent with lack of chromatin bivalency (Vastenhouw & Schier, ; Voigt et al , ). Importantly, Ser5 phosphorylation of poised RNAPII complexes at Polycomb‐repressed genes in ESCs is mediated by different kinases, ERK1/2 (Tee et al , ; Ma et al , ), instead of CDK7 which phosphorylates both S5p and S7p at active genes, irrespectively of pausing ratio (Akhtar et al , ; Glover‐Cutter et al , ). Loss of ERK1/2 activity in ESCs results in the loss of poised RNAPII‐S5p and decreased occupancy of PRC2 at Polycomb‐repressed developmental genes (Tee et al , ), suggesting a tight functional link between the presence of poised RNAPII‐S5p at Polycomb‐target genes and the recruitment of Polycomb.…”

Section: Introductionmentioning

confidence: 99%

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RNA polymerase II primes Polycomb‐repressed developmental genes throughout terminal neuronal differentiation

Ferrai

Triglia

Risner-Janiczek

et al. 2017

Molecular Systems Biology

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Polycomb repression in mouse embryonic stem cells (ESCs) is tightly associated with promoter co‐occupancy of RNA polymerase II (RNAPII) which is thought to prime genes for activation during early development. However, it is unknown whether RNAPII poising is a general feature of Polycomb repression, or is lost during differentiation. Here, we map the genome‐wide occupancy of RNAPII and Polycomb from pluripotent ESCs to non‐dividing functional dopaminergic neurons. We find that poised RNAPII complexes are ubiquitously present at Polycomb‐repressed genes at all stages of neuronal differentiation. We observe both loss and acquisition of RNAPII and Polycomb at specific groups of genes reflecting their silencing or activation. Strikingly, RNAPII remains poised at transcription factor genes which are silenced in neurons through Polycomb repression, and have major roles in specifying other, non‐neuronal lineages. We conclude that RNAPII poising is intrinsically associated with Polycomb repression throughout differentiation. Our work suggests that the tight interplay between RNAPII poising and Polycomb repression not only instructs promoter state transitions, but also may enable promoter plasticity in differentiated cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RNA polymerase II primes Polycomb‐repressed developmental genes throughout terminal neuronal differentiation

Ferrai

Triglia

Risner-Janiczek

et al. 2017

Molecular Systems Biology

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“…Through the activation of Mek and Erk, Fgf4 leads to the downregulation of Nanog at the transcriptional level, but also destabilizes Klf2 and Klf4 protein through Erk-dependent phosphorylation [22,23]. Moreover, Gsk3, which can mediate Wnt signalling has a differentiation promoting effect by repressing several pluripotency factors, [14], c [15], d [16], e [17], f [18], g [19], h [20], i [21], j [22], k [23], l [24], m [25], n [26], o [27].…”

Section: Sex Differences In Murine Embryonic Stem Cellsmentioning

confidence: 99%

“…Bivalency is characterized by the co-occurrence of the repressive and activating histone marks (H3K27me3 and H3K4me3) and is thought to poise developmental genes for upregulation upon exit from the naive pluripotent state. At a subset of bivalent promoters, Erk interacts with the X-linked factor Nono, which promotes Erk activity [15]. Also in human ES cells, Erk has been identified as a chromatin-bound factor and shown to co-localize with Elk1, a classic transcription factor downstream of Erk, at a subset of Elk1 target genes [45].…”

Section: The Pluripotency-associated Signalling Networkmentioning

confidence: 99%

X-chromosome dosage as a modulator of pluripotency, signalling and differentiation?

Schulz

2017

Phil. Trans. R. Soc. B

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Already during early embryogenesis, before sex-specific hormone production is initiated, sex differences in embryonic development have been observed in several mammalian species. Typically, female embryos develop more slowly than their male siblings. A similar phenotype has recently been described in differentiating murine embryonic stem cells, where a double dose of the X-chromosome halts differentiation until dosage-compensation has been achieved through X-chromosome inactivation. On the molecular level, several processes associated with early differentiation of embryonic stem cells have been found to be affected by X-chromosome dosage, such as the transcriptional state of the pluripotency network, the activity pattern of several signal transduction pathways and global levels of DNA-methylation. This review provides an overview of the sex differences described in embryonic stem cells from mice and discusses a series of X-linked genes that are associated with pluripotency, signalling and differentiation and their potential involvement in mediating the observed X-dosage–dependent effects. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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“…I then further focussed on proteins that had negative values in the ethanol treated samples I then used the K1ERC ChIPseq data generated in the previous chapter to correlate with NONO ChIPseq data (GSE73426). 234 I processed the data and identified 1208 Peaks in the NONO ChIPseq by MACS2.…”

Section: Klf1 May Interact With Dbhs Proteins Sfpq Nono and Pspc In mentioning

confidence: 99%

“Krüppeling Erythropoiesis”: KLF1 function in development and disease

Huang¹

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KLF1 is a three-fingered C2H2 transcription factor essential for the differentiation of definitive erythroid cells. KLF1 regulates the expression of many genes involved in this process and loss of Klf1 results in perinatal death due to anaemia and severe -thalassaemia in mice. The three C2H2 zinc-fingers of KLF1 are interconnected by two linker peptides. The first linker that connects the first and second zinc finger of KLF1 contains the conserved TGEKP sequence. The second linker connects the second and third zinc fingers and sequence TGHRP is more variant. In human patients, there have been multiple mutations identified in the 2 nd linker of KLF1. These mutations result in non-spherocytic haemolytic anaemia (NSHA) with microcytosis, and high foetal haemoglobin. While we understand pathology resulting from KLF1 mutations in these patients, very little is known about the precise molecular function of the 2 nd linker mutation, and in general, linker mutations across all C2H2 proteins. C2H2 zinc fingers are the largest class of DNA-binding proteins in the mammalian genome. They are characterized by the presence of two anti-parallel -sheets and an -helix (fold). Two cysteine and two histidine residues in the -fold coordinate a zinc molecule and are highly conserved across the family giving the zinc fingers their identity. Additionally, the -helix is directly involved in DNA contact through 3 amino acid residues at positions-1, +3 and +6 relative to the start of the helix. The linker peptide between each finger allows flexibility so that the -helix of each zinc-finger can contact DNA, while providing additional stability to these interactions through forming hydrogen bonds with the preceding -helix. This mechanism is known as c-capping and closes the 'frayed' c-terminus end of the -helix upon contacting DNA. Our laboratory recently identified the mommeD45 mutation from a mouse ENU mutagenesis screen for modifiers of an alpha-globin transgene. The mutation results in a transversion of the histidine to an arginine (H350R) residue in the second linker of KLF1. The mutation appears relatively benign in the heterozygous state. However homozygous D45 mice develop a mild anemic phenotype, including splenomegaly and microcytosis. To generate a model of NSHA in mice, like that observed in human patients, I crossed the mommeD45 mouse to a Klf1 heterozygous loss of function mouse to produce compound

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Nono, a Bivalent Domain Factor, Regulates Erk Signaling and Mouse Embryonic Stem Cell Pluripotency

Cited by 43 publications

References 49 publications

RNA polymerase II primes Polycomb‐repressed developmental genes throughout terminal neuronal differentiation

RNA polymerase II primes Polycomb‐repressed developmental genes throughout terminal neuronal differentiation

X-chromosome dosage as a modulator of pluripotency, signalling and differentiation?

“Krüppeling Erythropoiesis”: KLF1 function in development and disease

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