Overlapping functions of Krüppel-like factor family members: targeting multiple transcription factors to maintain the naïve pluripotency of mouse embryonic stem cells

Yamane, Mariko; Ohtsuka, Satoshi; Matsuura, Kazuki; Nakamura, Akira; Niwa, Hitoshi

doi:10.1242/dev.162404

Cited by 47 publications

(52 citation statements)

References 49 publications

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“…Further, as these TFs are specific to either of the two conditions, they might play a switch on-off mechanism in forming and maintaining the two pluripotent states ( Figure 10). This is in consistency with previous reports that the transcriptional network required to maintain the expression of core TFs, which is completely distinct in the two pluripotent states [3,47].…”

Section: Transcription Factor Screening Among Intra-modular Hub Genessupporting

confidence: 93%

“…The importance of zinc finger proteins in pluripotency and human development is well established. For example, the Krüppel-like factor family members KLF4 and KLF5 along with KLF2 has been found to be sufficient to support self-renewal and their removal can compromise it [47]. KLF4 and another blue module hub transcription factor TFCP2L1 are a part of the core gene regulatory network of naive pluripotency in mESC [48].…”

Section: Transcription Factor Screening Among Intra-modular Hub Genesmentioning

confidence: 99%

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Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

Ghosh

Som

2020

Preprint

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Pluripotent stem cells (PSCs) have been observed to occur in two distinct states -naive and primed. Both naive and primed state PSCs can give rise to tissues of all the three germ layers in vitro but differ in their potential to generate germline chimera in vivo. Understanding the molecular mechanisms that govern these two states of pluripotency in human can open up a plethora of opportunities for studying early embryonic development and in biomedical applications. In this work, we use weighted gene co-expression network (WGCN) approach to identify the key molecular makers and their interactions that define the two distinct pluripotency states. Signed-hybrid WGCN was reconstructed from transcriptomic data (RNA-seq) of naive and primed state pluripotent samples. Our analysis revealed two sets of genes that are involved in establishment and maintenance of naive (4791 genes) and primed (5066 genes) states. The naive state genes were found to be enriched for biological processes and pathways related to metabolic processes while primed state genes were associated with system development. Further, we identified the top 10% genes by intra-modular connectivity as hubs and the hub transcription factors for each group, thus providing a three-tier list of genes associated with naive and primed states of pluripotency in human. HIGHLIGHTS Weighted gene co-expression network analysis (WGCNA) identified 4791 and 5066 genes to be involved in naive and primed states of human pluripotency respectively.  Functional and pathway enrichment analysis revealed the naive genes were mostly related to metabolic processes and primed genes to system development. The top 10% genes based on intra-modular connectivity from each group were defined as hubs.  Identified 52 and 33 transcription factors among the naive and primed module hubs respectively. The transcription factors might play a switch on-off mechanism in induction of the two pluripotent states.

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Section: Transcription Factor Screening Among Intra-modular Hub Genessupporting

confidence: 93%

Section: Transcription Factor Screening Among Intra-modular Hub Genesmentioning

confidence: 99%

Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

Ghosh

Som

2020

Preprint

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“…Our results identify a functional overlap between two members of the same family of orphan nuclear receptors, Esrrb and Nr5a2, in supporting pluripotency in ESCs. Similar redundant functions have been described for another family of auxiliary pluripotency TFs, KLFs (Di Giammartino et al, 2019;Yamane et al, 2018). The individual deletion of Klf4, Klf2 and Klf5 is compatible with self-renewal in ESCs, but not the concomitant loss of all three TFs.…”

Section: Discussionsupporting

confidence: 60%

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

Festuccia

Owens

Chervova

et al. 2020

Preprint

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The maintenance of pluripotency in mouse embryonic stem cells (ESCs) is governed by the action of an interconnected network of transcription factors. Among them, only Oct4 and Sox2 have been shown to be strictly required for the self-renewal of ESCs and pluripotency, particularly in culture conditions where differentiation cues are chemically inhibited. Here, we report that the conjunct activity of two orphan nuclear receptors, Esrrb and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve ESCs. By occupying a large common set of regulatory elements, these two factors control the binding of Oct4, Sox2 and Nanog to DNA. Consequently, in their absence the pluripotency network collapses and the transcriptome is substantially deregulated, leading to the differentiation of ESCs. Altogether, this work identifies orphan nuclear receptors, previously thought to be performing supportive functions, as a new set of core regulators of naïve pluripotency.

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“…Zfp281, in contrast, acts bidirectionally as it drives ESC differentiation and inhibits reprogramming of EpiSCs. Notably, this is inverse to the activity of reprogramming TFs, e.g., Klf4 and Esrrb, that induce and consolidate the naïve ESC state (Guo et al, 2009;Niwa et al, 2009;Festuccia et al, 2012;Martello et al, 2012;Yamane et al, 2018).…”

Section: Zfp281 Is a Bidirectional Esc-episc Transition Regulatormentioning

confidence: 99%

Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

et al. 2019

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Developmental cell fate specification is a unidirectional process that can be reverted in response to injury or experimental reprogramming. Whether differentiation and de-differentiation trajectories intersect mechanistically is unclear. Here, we performed comparative screening in lineage-related mouse naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), and identified the constitutively expressed zinc finger transcription factor (TF) Zfp281 as a bidirectional regulator of cell state interconversion. We showed that subtle chromatin binding changes in differentiated cells translate into activation of the histone H3 lysine 9 (H3K9) methyltransferase Ehmt1 and stabilization of the zinc finger TF Zic2 at enhancers and promoters. Genetic gain-of-function and loss-of-function experiments confirmed a critical role of Ehmt1 and Zic2 downstream of Zfp281 both in driving exit from the ESC state and in restricting reprogramming of EpiSCs. Our study reveals that cell type-invariant chromatin association of Zfp281 provides an interaction platform for remodeling the cisregulatory network underlying cellular plasticity.

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Overlapping functions of Krüppel-like factor family members: targeting multiple transcription factors to maintain the naïve pluripotency of mouse embryonic stem cells

Cited by 47 publications

References 49 publications

Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

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