KLF7 Regulates Satellite Cell Quiescence in Response to Extracellular Signaling

Wang, Xiaobin; Shen, Qingwu; Wang, Jie; Zhang, Zhiguo; Fu, Feng; Chen, Ting; Zhang, Yanyan; Wei, Huan; Li, Zhongwen; Wang, Xinxia; Wang, Yizhen

doi:10.1002/stem.2346

Cited by 29 publications

(25 citation statements)

References 58 publications

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“…However, our findings and other recent reports have begun to reveal novel signaling effects and preferential targets for NOTCH3 (Baeten and Lilly, 2015;Cui et al, 2013;Wang et al, 2016). As it stands, NOTCH3 appears to be unique among the receptors.…”

Section: Potential Downstream Effects Of Notch Activitysupporting

confidence: 61%

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

Frank

Berger

Ljungman

et al. 2017

Journal of Cell Science

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Many pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that regulation of NOTCH3 by the p38 MAPK family (hereafter p38-MAPK), via MYC, is required for luminal differentiation. Inhibition (SB202190 and BIRB796) or knockdown of p38α (also known as MAPK14) and/or p38δ (also known as MAPK13) prevented proper differentiation. Additionally, treatment with a γ-secretase inhibitor (RO4929097) or knockdown of NOTCH1 and/or NOTCH3 greatly impaired differentiation and caused luminal cell death. Constitutive p38-MAPK activation through MKK6(CA) increased NOTCH3 (but not NOTCH1) mRNA and protein levels, which was diminished upon MYC inhibition (10058-F4 and JQ1) or knockdown. Furthermore, we validated two NOTCH3 enhancer elements through a combination of enhancer (e)RNA detection (BruUV-seq) and luciferase reporter assays. Finally, we found that the NOTCH3 mRNA half-life increased during differentiation or upon acute p38-MAPK activation. These results reveal a new connection between p38-MAPK, MYC and NOTCH signaling, demonstrate two mechanisms of NOTCH3 regulation and provide evidence for NOTCH3 involvement in prostate luminal cell differentiation.

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Section: Potential Downstream Effects Of Notch Activitysupporting

confidence: 61%

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

Frank

Berger

Ljungman

et al. 2017

Journal of Cell Science

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“…As an additional control, qPCR for putative KLF6-downstream genes was also performed after transfection with mutant forms of KLF6. Transcriptional activity of KLF6 and −7 has been previously shown to be sensitive to acetylation of two lysines (K) located in the first zinc finger of the DNA binding domain (Li et al, 2005; Wang et al, 2016). Accordingly, lysines 209 and 213 of KLF6 were mutated to either arginine (R) or glutamine (Q) to block or mimic the effects of acetylation, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Wang¹,

Mehra²,

Simpson³

et al. 2018

Preprint

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Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration in the central nervous system, but the underlying mechanisms are unclear. KLF6 and −7 share nearly identical DNA binding domains and stand out as the only known growth-promoting family members. Here we confirm that similar to KLF7, expression of KLF6 declines during postnatal cortical development and that forced re-expression of KLF6 in corticospinal tract neurons of adult female mice enhances axon regeneration after cervical spinal injury. Unlike KLF7, however, these effects were achieved with wildtype KLF6, as opposed constitutively active mutants, thus simplifying the interpretation of mechanistic studies. To clarify the molecular basis of growth promotion, RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in cortical neurons. Network analysis of these genes revealed sub-networks of downregulated genes that were highly enriched for synaptic functions, and sub-networks of upregulated genes with functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis and transport, and bioenergetics. The promoter regions of KLF6-sensitive genes showed enrichment for the binding sequence of STAT3, a previously identified regeneration-associated gene. Notably, co-expression of constitutively active STAT3 along with KLF6 in cortical neurons produced synergistic increases in neurite length. Finally, genome-wide ATAC-seq footprinting detected frequent co-binding by the two factors in pro-growth gene networks, indicating co-occupancy as an underlying mechanism for the observed synergy. These findings advance understanding of KLF-stimulated axon growth and indicate functional synergy of KLF6 transcriptional effects with those of STAT3.SIGNIFICANCE STATEMENTThe failure of axon regeneration in the CNS limits recovery from damage and disease. These findings show the transcription factor KLF6 to be a potent promoter of axon growth after spinal injury, and more importantly clarify the underlying transcriptional changes. In addition, bioinformatics analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting confirmed frequent co-occupancy. Co-expression of the two factors yielded synergistic elevation of neurite growth in primary neurons. These data point the way toward novel transcriptional interventions to promote CNS regeneration.

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“…This in accordance with a recent study showing that satellite cells maintained in an undifferentiated stage by leukemia inhibitory factor engrafted more efficiently 49 . The mechanisms involved in the regulation of muscle stem cell quiescence are not fully identified yet, but mechanisms involving Sprouty1 50, 51 , autophagy 52 , notch signaling 53 , miRNAs 54 , Kruppel-like factor 7 55 and epigenetic events 56 could favor quiescent MRC emergence.…”

Section: Discussionmentioning

confidence: 99%

Human myogenic reserve cells are quiescent stem cells that contribute to muscle regeneration after intramuscular transplantation in immunodeficient mice

Laumonier

Bermont

Hoffmeyer

et al. 2017

Sci Rep

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Satellite cells, localized within muscles in vivo, are Pax7+ muscle stem cells supporting skeletal muscle growth and regeneration. Unfortunately, their amplification in vitro, required for their therapeutic use, is associated with reduced regenerative potential. In the present study, we investigated if human myogenic reserve cells (MRC) obtained in vitro, represented a reliable cell source for muscle repair. For this purpose, primary human myoblasts were freshly isolated and expanded. After 2 days of differentiation, 62 ± 2.9% of the nuclei were localized in myotubes and 38 ± 2.9% in the mononucleated non-fusing MRC. Eighty percent of freshly isolated human MRC expressed a phenotype similar to human quiescent satellite cells (CD56+/Pax7+/MyoD−/Ki67− cells). Fourteen days and 21 days after cell transplantation in immunodeficient mice, live human cells were significantly more numerous and the percentage of Pax7+/human lamin A/C+ cells was 2 fold higher in muscles of animals injected with MRC compared to those injected with human myoblasts, despite that percentage of spectrin+ and lamin A/C+ human fibers in both groups MRC were similar. Taken together, these data provide evidence that MRC generated in vitro represent a promising source of cells for improving regeneration of injured skeletal muscles.

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KLF7 Regulates Satellite Cell Quiescence in Response to Extracellular Signaling

Cited by 29 publications

References 58 publications

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Human myogenic reserve cells are quiescent stem cells that contribute to muscle regeneration after intramuscular transplantation in immunodeficient mice

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