Molekulare Kontrolle der Brite Adipogenese: Identifikation neuer Zelloberflächenmarker, Regulatoren der Transkription und Funktionskomponenten
Zusammenfassung der Projektergebnisse
The recruitment of thermogenic brite adipocytes within white adipose tissue (WAT) attenuates obesity and metabolic comorbidities, arousing great interest in understanding the intricate regulatory mechanisms underlying this process. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network as well as long noncoding RNAs (lncRNAs) coordinating this cellular process. Brite adipogenesis demands complex spatial and temporal orchestration of multiple regulatory factors. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. LncRNAs are emerging as a versatile class of modulators able to control many steps within the differentiation machinery including chromatin accessibility, gene transcription, splicing and translation. Here we identified and characterized nuclear the lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a bi-functional regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by controlling gene transcription and splicing of the key browning factor Prdm16 towards its thermogenic gene program promoting transcript isoform. Therefore, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function. Collectively, the findings identified in this project therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue.
Projektbezogene Publikationen (Auswahl)
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(2018) Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation. Cell; 175(6):1561-1574
Li Y, Schnabl K, Gabler SM, Willershäuser M, Reber J, Karlas A, Laurila S, Lahesmaa M, U Din M, Bast-Habersbrunner A, Virtanen KA, Fromme T, Bolze F, O'Farrell LS, Alsina- Fernandez J, Coskun T, Ntziachristos V, Nuutila P, Klingenspor M
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(2019) A dual Ucp1 reporter mouse model for imaging and quantitation of brown and brite fat recruitment. Mol Metab 20:14-27
Wang H, Willershäuser M, Karlas A, Gorpas D, Reber J, Ntziachristos V, Maurer S, FrommeT, Li Y, Klingenspor M
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(2019) Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning. Cell reports 29: 4099-4113.e4095
Li Y, Schwalie PC, Bast-Habersbrunner A, Mocek S, Russeil J, Fromme T, Deplancke B, Klingenspor M
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(2020). Isolation, Culture, and Functional Analysis of Murine Thermogenic Adipocytes. STAR Protocols, 100118
Oeckl, J., Bast-Habersbrunner, A., Fromme, T., Klingenspor, M., & Li, Y.
