A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation

Nishimura, Ken; Aizawa, Shiho; Nugroho, Fransiska Liliani; Shiomitsu, Emi; Tran, Thi Hai Yen; Bui, Phuong Linh; Borisova, Evgeniia; Sakuragi, Yuta; Takada, Hitomi; Kurisaki, Akira; Hayashi, Yohei; Fukuda, Aya; Nakanishi, Mahito; Hisatake, Koji

doi:10.1016/j.stemcr.2017.01.026

Cited by 37 publications

(57 citation statements)

References 46 publications

(77 reference statements)

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“…Consistent with these results, KDM5B was identified as a critical factor of SCNT reprogramming, and its overexpression significantly reduced four-cell arrest during the development of mouse cloned embryos. Of these genes, TCL1 participates in the development of early embryos in mice, 45 and its overexpression can considerably enhance the reprogramming efficiency in mouse iPSCs 46,47 ; SUPT4H1 5 and HNF1B 12 were demonstrated to be essential for bovine EGA. 29 Compared with the method in which positive clones are selected after cell transfection, the microinjection of KDM5B mRNA employed in the present study is a simple and rapid method.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional memory inherited from donor cells is a developmental defect of bovine cloned embryos

Zhou

Zhang

et al. 2019

FASEB j.

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Studies on the effects of transcriptional memory on clone reprogramming in mammals are limited. In the present study, we observed higher levels of active histone H3 lysine 4 trimethylation (H3K4me3 and 5‐hydroxymethylcytosine) and repressive (5‐methylcytosine) epigenetic modifications in bovine early cloned embryos than in in vitro fertilized embryos. We hypothesized that aberrant epigenetic modification may result in transcriptional disorders in bovine somatic cell nuclear transfer (SCNT) embryos. RNA sequencing results confirmed that both abnormal transcriptional silencing and transcriptional activation are involved in bovine SCNT reprogramming. The cloned embryos exhibited excessive transcription in RNA processing‐ and translation‐related genes as well as transcriptional defects in reproduction‐related genes whose transcriptional profiles were similar to those in donor cells. These results demonstrated the existence of active and silent memory genes inherited from donor cells in early bovine SCNT embryos. Further, H3K4me3‐specific demethylase 5B (KDM5B) mRNA was injected into the reconstructed embryos to reduce the increased H3K4me3 modification. KDM5B overexpression not only reduced the transcriptional level of active memory genes, but also promoted the expression of silent memory genes; in particular, it rescued the expression of multiple development‐related genes. These results showed that transcriptional memory acts as a reprogramming barrier and KDM5B improves SCNT reprogramming via bidirectional regulation effects on transcriptional memory genes in bovines.

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Section: Discussionmentioning

confidence: 99%

Transcriptional memory inherited from donor cells is a developmental defect of bovine cloned embryos

Zhou

Zhang

et al. 2019

FASEB j.

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“…PNPase is a type-I IFN induced gene [ 41 ] and over-expression at supra-physiologic levels affects reactive oxygen species (ROS) generation and NF-κB activation [ 42 ]. Recently, PNPase was linked to metabolism control during somatic cell reprogramming to induced pluripotent stem cells [ 43 , 44 ]. In humans, PNPase mutations genetically link to hereditary hearing loss, encephalomyopathy, and axonal and auditory neuropathy, gut disturbances, chorioretinal defects, Leigh syndrome, and delayed myelination [ 45 – 50 ].…”

Section: Introductionmentioning

confidence: 99%

PNPase knockout results in mtDNA loss and an altered metabolic gene expression program

et al. 2018

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Polynucleotide phosphorylase (PNPase) is an essential mitochondria-localized exoribonuclease implicated in multiple biological processes and human disorders. To reveal role(s) for PNPase in mitochondria, we established PNPase knockout (PKO) systems by first shifting culture conditions to enable cell growth with defective respiration. Interestingly, PKO established in mouse embryonic fibroblasts (MEFs) resulted in the loss of mitochondrial DNA (mtDNA). The transcriptional profile of PKO cells was similar to rho0 mtDNA deleted cells, with perturbations in cholesterol (FDR = 6.35 x 10−13), lipid (FDR = 3.21 x 10−11), and secondary alcohol (FDR = 1.04x10-12) metabolic pathway gene expression compared to wild type parental (TM6) MEFs. Transcriptome analysis indicates processes related to axonogenesis (FDR = 4.49 x 10−3), axon development (FDR = 4.74 x 10−3), and axonal guidance (FDR = 4.74 x 10−3) were overrepresented in PKO cells, consistent with previous studies detailing causative PNPase mutations in delayed myelination, hearing loss, encephalomyopathy, and chorioretinal defects in humans. Overrepresentation analysis revealed alterations in metabolic pathways in both PKO and rho0 cells. Therefore, we assessed the correlation of genes implicated in cell cycle progression and total metabolism and observed a strong positive correlation between PKO cells and rho0 MEFs compared to TM6 MEFs. We quantified the normalized biomass accumulation rate of PKO clones at 1.7% (SD ± 2.0%) and 2.4% (SD ± 1.6%) per hour, which was lower than TM6 cells at 3.3% (SD ± 3.5%) per hour. Furthermore, PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase. Combined, our study reports that knockout of a mitochondrial nuclease results in mtDNA loss and suggests that mtDNA maintenance could provide a unifying connection for the large number of biological activities reported for PNPase.

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“…Mechanistically, KLF4 determines mitochondrial function in several diseases with metabolic disorders. 24,25 To this end, present study further investigates whether KLF4 participated in obesity-in- Figure 4F, the citrate synthase activity of extracted renal mitochondria was decreased in obese mice, but overexpression of Klf4 significantly recovered its level in HFD-fed mice (P < .05). HFD also significantly decreased mitochondrial ATP production by 58.3%, whereas the relative ATP levels were obviously up-regulated in AAV-Klf4-treated obese mice ( Figure 4G, P < .05).…”

Section: Overexpression Of Klf4 Improves High-fat Diet-induced Renamentioning

confidence: 94%

Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

Jin

Pan

et al. 2019

J Cellular Molecular Medi

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Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel‐like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary‐induced renal injuries and underlying mechanisms in obesity. Through utilizing high‐fat diet‐fed mice and human renal biopsies, we provided the physiological roles of KLF4 in protecting against obesity‐related nephropathy. Decreased levels of renal KLF4 were positively correlated with dietary‐induced renal dysfunction, including increased levels of creatinine and blood urea nitrogen. Overexpression of renal KLF4 suppressed inflammatory response in palmitic acid‐treated mouse endothelial cells. Furthermore, overexpressed KLF4 also attenuated dietary‐induced renal functional disorders, abnormal structural remodelling and inflammation. Mechanistically, KLF4 maintained renal mitochondrial biogenesis and activities to combat obesity‐induced mitochondrial dysfunction. In clinical renal biopsies and plasma, the renal Klf4 level was negatively associated with circulating levels of creatinine but positively associated with renal creatinine clearance. In conclusions, the present findings firstly supported that renal KLF4 played an important role in combating obesity‐related nephropathy, and KLF4/mitochondrial function partially determined the energy homeostasis in chronic kidney diseases.

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A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation

Cited by 37 publications

References 46 publications

Transcriptional memory inherited from donor cells is a developmental defect of bovine cloned embryos

Transcriptional memory inherited from donor cells is a developmental defect of bovine cloned embryos

PNPase knockout results in mtDNA loss and an altered metabolic gene expression program

Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

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