KLF15 and PPARδ cooperativity in the orchestration of lipid metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA820707 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18503828_1.fastq.gz | Fastqsanger.gz | |||
| SRR18503828_2.fastq.gz | Fastqsanger.gz | |||
| SRR18503829_1.fastq.gz | Fastqsanger.gz | |||
| SRR18503829_2.fastq.gz | Fastqsanger.gz | |||
| SRR18503830_1.fastq.gz | Fastqsanger.gz |
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Project description:We characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ co-localize genome-wide, interact, and are dependent on one another to exert their transcriptional effects on target genes.
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Project description:Skeletal muscle dynamically regulates systemic nutrient homeostasis through transcriptional adaptations to physiological cues. In response to changes in the metabolic environment (e.g., alterations in circulating glucose or lipid levels), networks of transcription factors and coregulators are recruited to specific genomic loci to fine-tune homeostatic gene regulation. Elucidating these mechanisms is of particular interest as these gene regulatory pathways can serve as potential targets to treat metabolic disease. The zinc-finger transcription factor Krüppel-like factor 15 (KLF15) is a critical regulator of metabolic homeostasis; however, its genome-wide distribution in skeletal muscle has not been previously identified. Here, we characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We also identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ colocalize genome-wide, physically interact, and are dependent on one another to exert their transcriptional effects on target genes. These findings reveal that skeletal muscle KLF15 plays a critical role in metabolic adaptation through its direct actions on target genes and interactions with other nodal transcription factors such as PPARδ.
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Project description:Angiogenesis is a dynamic process fine-tuned by transcription factors in endothelial cells. The Krüpple-like factor 15 (KLF15)-mediated transcriptional regulation mechanism is critical for cardiovascular diseases. However, the role of endothelial KLF15 in governing angiogenesis remains unknown.KLF15 and vasorin (VASN) were deleted from endothelial cells using tamoxifen-inducible Cdh5-promoter-driven Cre recombinase in EC-KLF15 KO and EC-VASN KO mice, respectively. EC-KLF15 KO, EC-VASN KO and control mice were subjected to retinal angiogenesis or tumor cell transplantation. The RNA sequencing (RNA-seq), ATAC-seq, and ChIP-seq were conducted to identify VASN as a downstream effector of KLF15. Cell proliferation, wound healing, tube formation, and sprouting assays were performed to delineate endothelial cell function. In EC-KLF15 KO mice and adenovirus-mediated KLF15 overexpression mice, we showed that KLF15 negatively regulated retinal angiogenesis, as confirmed in cultured endothelial cells. KLF15 opened chromatin, bound to the promoters of GC-rich sequences, and transactivated the expression of VASN. Subsequently, VASN suppressed endothelial angiogenic function which was essential for Dll4-induced Notch1 signaling activation. Moreover, increased expression of VASN in EC-KLF15 KO mice suppressed retinal angiogenesis, which was attenuated by γ-secretase inhibitor. EC-VASN KO mice recapitulated the promotion of retinal angiogenesis in EC-KLF15 KO mice. Finally, the EGF-like domain of VASN was essential for its interaction with Notch1, and VASN EGF-like domain-derived peptides activated Notch1 signaling and suppressed angiogenesis.The KLF15/VASN axis negatively regulates angiogenesis by activating Notch1 signaling. KLF15 and VASN in endothelial cells might represent novel therapeutic targets for the treatment of impaired angiogenesis-related diseases and tumors.
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