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- W4313366113 abstract "Abstract Kupffer cells have specialized roles supporting the environment of the liver during homeostasis and disease. However, the key regulatory elements governing these behaviors are unknown. Using scRNA-seq, we found diversification of Kupffer cells and recruitment of additional macrophage subtypes during nonalcoholic steatohepatitis (NASH). A significant source of macrophage heterogeneity during NASH was traced to Cx3cr1 expressing monocytes. Further, macrophage subsets were localized in distinct niches, suggesting environmental specification as a key determinant of macrophage heterogeneity. We profiled chromatin accessibility of the major NASH associated macrophage populations to identify transcription factors governing their environmental specification. These results predict greater NFκB, RUNX, and AP1 activity in recruited hepatic macrophages compared to Kupffer cells. Surprisingly, we found minimal significant chromatin accessibility changes comparing Kupffer cells from healthy mice to mice with NASH, even though several thousand genes were differentially expressed. Instead, NASH led to altered chromatin activity, as measured by H3K27ac ChIP-seq, at Kupffer cell enhancer regions. A binding element for LXR (liver X receptor) was the top transcription factor motif identified in Kupffer cell enhancers with reduced activity during NASH. Furthermore, LXRα was required to maintain expression of a unique gene signature defining healthy Kupffer cells. Thus, our studies establish for the first time gene regulatory events controlling diverse hepatic macrophages during homeostasis and NASH." @default.
- W4313366113 created "2023-01-06" @default.
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- W4313366113 date "2019-05-01" @default.
- W4313366113 modified "2023-09-23" @default.
- W4313366113 title "Exploiting altered enhancer landscapes to decode pathogenic changes in gene expression of diverse hepatic macrophages" @default.
- W4313366113 doi "https://doi.org/10.4049/jimmunol.202.supp.59.2" @default.
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