Our laboratory applies state-of-the-art mass spectrometry and compu-62tational methods for proteome analysis in complex biological systems, such as white adipose tissue (WAT). We have developed research themes on the molecular mechanism of WAT expansion. Specifically, we are interested in the molecular and functional heterogeneity of adipocyte progenitor populations, as well as how adipocytes, precursors and immune cells coordinately regulate the function of WAT.To investigate sex- and depot (i.e. visceral or subcutaneous WAT)-dependent adipocyte progenitor cell heterogeneity, we performed a multilayered omics analysis to dissect adipose progenitor cell heterogeneity in three dimensions: progenitor subpopulation, sex, and anatomical localization. We have quantified 4870 proteins and 15477 transcripts. The data are freely accessible as a resource at “Pread Profiler” (http://preadprofiler.net/). Both proteomic and transcrip-tomic data clearly separated the eight cell populations (Figure). However, it is remarkable that the manner in which the populations can be grouped depends on the layer of analysis. Clustering based on proteomic data highlights the functional similarities and differences between the subgroups of cells, whereas clustering of cell populations based on transcript levels was driven by their in-herent depot-dependent differences in gene expression.In addition, we found that transcript levels are not indicative of cognate protein levels in many scenarios. Thus, changes in a certain transcript may not necessarily be reflected at the protein level. Surprisingly, both sex and depot had an impact on protein-transcript correlation.Our data revealed functional pathways that could discriminate cell popula-tions. We found that PPARg phosphorylation underlies sex differences in iWAT APC differentiation. Furthermore, we discovered the importance of glutathione metabolism and AhR signaling in regulating progenitor cell fate and function. This multilayered omics analysis provides unprecedented insights into adipose stromal cell heterogeneity and highlights the benefit of complementary pro-teomics to support findings from scRNA-seq studies.Figure: A multilayered omics analysis reveals sex- and depot-dependent adipose stromal cell heterogeneityWe describe a comprehensive and integrated dataset that details the transcriptomic and proteomic heteroge-neity of adipose tissue progenitors in three dimensions: cell type (WAT PDGFR+ stromal cell subpopulations), anatomical localization (visceral and subcutaneous adipose depots), and sex (male and female mice). We have quantified 4870 proteins and 15477 transcripts across 24 samples, including 4540 protein-transcript pairs. Our data unveil molecular signatures defining sex differences in preadipocyte differentiation and identify regulatory pathways that functionally distinguish adi-pose progenitor subpopulations.Recent Major PublicationsShan B, Barker S. C, Shao M, Zhang Q, Gupta K. R, Wu Y. Multilayered omics reveal Sex- and depot-dependent adipose progenitor cell heterogeneity. Cell Metab 34, 783-799.e7 (2022)Zhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, ... Honjo T, Fagarasan S. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471-476 (2021)Shao M, Hepler C, Zhang Q, Shan B, Vishvanath L, Ger-vaise H. H, Zhao S, Yu A A, Wu Y, Strand W. D, and Rana K. Gupta. Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity. Cell Stem Cell 28, 1-17 (2021)YCI Laboratory for Next-Generation ProteomicsYoung Chief Investigator: Yibo Wu
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