A dynamic interplay of enhancer elements regulates <i>Klf4</i> expression in naïve pluripotency

Xie, Liangqi; Torigoe, Sharon E.; Jian-yun, Xiao; Daniel, H; Li, Li; Davis, Fred P.; Dong, Peng; Marie-Nelly, Hervé; Grimm, Jonathan B.; Lavis, Luke D.; Darzacq, Xavier; Cattoglio, Claudia; Liu, Zhe; Tjian, Robert

doi:10.1101/gad.303321.117

Cited by 55 publications

(68 citation statements)

References 37 publications

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“…A functional hierarchy can be further inferred from the site-specific deletion of the EBF1-binding site in the Cd79a promoter, which abrogated EBF1 occupancy but also impaired binding of Pax5 and PU.1 at nonadjacent sites. This observation is similar to the recent analysis of the Klf4 enhancer in embryonic stem cells in which deletion of the Oct4/Sox2 site reduced chromatin accessibility and prevented the binding of STAT3 and ESRRB (Xie et al 2017). Conversely, deletion of STAT3-or ESRRBbinding sites impaired Klf4 expression but did not affect Oct4/Sox2 binding.…”

Section: Dynamics Of B-lineage-associated Transcription Factors and Fsupporting

confidence: 77%

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

et al. 2018

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B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage-inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1 −/− pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming.

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Section: Dynamics Of B-lineage-associated Transcription Factors and Fsupporting

confidence: 77%

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

et al. 2018

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“…For ES cells maintained in LIF/serum, Klf4 has been shown to be regulated by three enhancers 54-68kb downstream of the gene; deletion of this region was found to reduce Klf4 transcription by 90%, greatly affecting KLF4 protein levels (Xie et al, 2017). For ES cells maintained in the more naïve state by LIF/2i, we determined that although the enhancers remain important for maintaining transcript levels, functional KLF4 protein is maintained in the absence of the enhancers.…”

Section: Lif/2imentioning

confidence: 94%

“…Differentiation of embryonic stem (ES) cells requires disruption to the regulatory network that maintains pluripotency gene expression. Kruppel-like factor 4 (KLF4), a member of the Kruppellike factor family of conserved zinc finger transcription factors, is known to interact with the core network of pluripotency transcription factors (NANOG,SOX2 and OCT4) in order to regulate genes required for maintenance of pluripotency and reprogramming (Dhaliwal et al, 2018;Wei et al, 2013;Wei et al, 2009;Xie et al, 2017;Zhang et al, 2010). Sustained expression of constitutively nuclear KLF4 prevents differentiation of ES cells indicating that a loss of KLF4 protein function is required for differentiation (Dhaliwal et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These enhancers are often located multi kb distances from the genes they regulate and form physical loops with their target gene promoters (Carter et al, 2002;Schoenfelder et al, 2015;Tolhuis et al, 2002). In pluripotent ES cells, specific enhancers have been identified that regulate Sox2, Klf4,Nanog and Oct4 (Pou5f1) at the transcriptional level (Blinka et al, 2016;Li et al, 2014;Xie et al, 2017;Yeom et al, 1996;Zhou et al, 2014). In addition to these intrinsic mechanisms that regulate the expression of pluripotency transcription factors, the balance between maintaining the pluripotent state and inducing differentiation is also modulated by cell extrinsic factors and cell signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

“…Leukemia inhibitory factor (LIF) maintains the pluripotent state by activating JAK-STAT signaling causing phosphorylation and activation of STAT3 (Matsuda et al, 1999;Niwa et al, 1998). Activated STAT3 induces transcription of Klf4 through binding to the enhancers downstream of Klf4 (Hall et al, 2009;Xie et al, 2017;Zhang et al, 2010). In addition, dual inhibition (2i, GSK3 and MEK inhibition) maintains ES cells in a naïve state closest to that of the precursor cells from the pluripotent epiblast of pre-implantation embryos (Nichols and Smith, 2009;Tosolini and Jouneau, 2016;Wray et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Dhaliwal

Abatti

Mitchell

2019

Preprint

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Embryonic stem (ES) cells are regulated by a network of transcription factors which maintain the pluripotent state. Differentiation relies on downregulation of pluripotency transcription factors disrupting this network. While investigating transcriptional regulation of the pluripotency transcription factor Klf4, we observed homozygous deletion of distal enhancers caused 17 fold decrease in Klf4 transcript but surprisingly decreased protein levels by less than 2 fold indicating post-transcriptional control of KLF4 protein overrides transcriptional control. The lack of sensitivity of KLF4 to transcription is due to high protein stability (half-life >24hr). This stability is context dependent and disrupted during differentiation, evidenced by a shift to a half-life of <2hr. KLF4 protein stability is maintained through interaction with other pluripotency transcription factors (NANOG, SOX2 and STAT3) that together facilitate association of KLF4 with RNA polymerase II. In addition, the KLF4 DNA binding and transactivation domains are required for optimal KLF4 protein stability. Post-translational modification of KLF4 destabilizes the protein as cells exit the pluripotent state and mutations that prevent this destabilization also prevent differentiation. These data indicate the core pluripotency transcription factors are integrated by post-translational mechanisms to maintain the pluripotent state, and identify mutations that increase KLF4 protein stability while maintaining transcription factor function.

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Stat3 activation is critical for pluripotency maintenance

Zhang

Wang

et al. 2018

Journal Cellular Physiology

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Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription with many important functions, including regulation of cell proliferation, differentiation, survival, angiogenesis, and immune response. Besides, it plays critical roles in regulating the pluripotency. With the ability of self-renewal and differentiation, embryonic stem (ES) cells provide an unlimited source for cell transplantation. ES cells can maintain its undifferentiated state with leukemia inhibitory factor, the role which is achieved by the activation of the Stat3 pathway. Moreover, Stat3 activation is necessary for the naïve state maintenance of the ES cells and somatic stem cells reprogramming. This study presents an overview of the critical roles of Stat3 activation in the pluripotency maintenance of ES cells, somatic cell reprogramming, and naïve-primed pluripotent states conversion of ES cells.

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A dynamic interplay of enhancer elements regulates Klf4 expression in naïve pluripotency

Cited by 55 publications

References 37 publications

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming

KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control

Stat3 activation is critical for pluripotency maintenance

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