Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle.
Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle.
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转录因子KLF15和PPARδ协同协调骨骼肌脂质代谢的全基因组调控。
DOI：
10.1016/j.jbc.2022.101926
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Jain, Mukesh K.
中科院分区：
文献类型：
--
作者：
Fan, Liyan;Sweet, David R.;Fan, Erica K.;Prosdocimo, Domenick A.;Madera, Annmarie;Jiang, Zhen;Padmanabhan, Roshan;Haldar, Saptarsi M.;Vinayachandran, Vinesh;Jain, Mukesh K.
骨骼肌通过对生理线索的转录适应动态调节全身营养稳态。响应于代谢环境的变化（例如，循环葡萄糖或脂质水平的改变），转录因子和辅助调节因子的网络被募集到特定的基因组位点以微调稳态基因调节。阐明这些机制是特别感兴趣的，因为这些基因调控途径可以作为治疗代谢疾病的潜在靶点。锌指转录因子Krüppel样因子15（KLF 15）是代谢稳态的关键调节因子;然而，其在骨骼肌中的全基因组分布以前尚未确定。在这里，我们在体内骨骼肌中的KLF 15顺式组的特点，发现大多数KLF 15结合定位于远端基因间区域，并与昼夜节律和脂质代谢相关的基因。我们还确定了KLF 15和核受体PPARδ在脂质代谢基因程序调控中的关键相互依赖性。我们进一步证明了KLF 15和PPARδ共定位于全基因组，物理相互作用，并相互依赖，以发挥其对靶基因的转录作用。这些发现揭示了骨骼肌KLF 15通过其对靶基因的直接作用以及与其他节点转录因子如PPARδ的相互作用在代谢适应中起关键作用。
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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影响因子：
3.4
作者：
Kim, Gyuri;Kim, Jae Hyeon
通讯作者：
Kim, Jae Hyeon
影响因子：
13.6
作者：
Jiang Z;Elsarrag SZ;Duan Q;LaGory EL;Wang Z;Alexanian M;McMahon S;Rulifson IC;Winchester S;Wang Y;Vaisse C;Brown JD;Quattrocelli M;Lin CY;Haldar SM
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Haldar SM
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5.4
作者：
Grygiel-Górniak B
通讯作者：
Grygiel-Górniak B
影响因子：
29
作者：
Fan W;Waizenegger W;Lin CS;Sorrentino V;He MX;Wall CE;Li H;Liddle C;Yu RT;Atkins AR;Auwerx J;Downes M;Evans RM
通讯作者：
Evans RM
DOI：
10.1073/pnas.012610299
发表时间：
2002-01-08
影响因子：
11.1
作者：
Barak, Y;Liao, D;Evans, RM
通讯作者：
Evans, RM