Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages
Martina I. Lefterova,David J. Steger,David Zhuo,Mohammed Qatanani,Shannon E. Mullican,Geetu Tuteja,Elisabetta Manduchi,Gregory R. Grant,Mitchell A. Lazar +8 more
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TLDR
The nuclear receptor peroxisome proliferator activator receptor γ (PPARγ) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use.Abstract:
The nuclear receptor peroxisome proliferator activator receptor γ (PPARγ) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPARγ is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPARγ binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPARγ cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPARγ colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPARγ, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPARγ function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPARγ binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation.read more
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PPARγ signaling and metabolism: the good, the bad and the future
Maryam Ahmadian,Jae Myoung Suh,Nasun Hah,Christopher Liddle,Annette R. Atkins,Michael Downes,Ronald M. Evans +6 more
TL;DR: This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
Journal ArticleDOI
The selection and function of cell type-specific enhancers
TL;DR: The human body contains several hundred cell types, all of which share the same genome, and much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers, which influences the functions of enhancers and super-enhancers.
Journal ArticleDOI
Remodeling of the Enhancer Landscape during Macrophage Activation Is Coupled to Enhancer Transcription
Minna U. Kaikkonen,Nathanael J. Spann,Sven Heinz,Casey E. Romanoski,Karmel A. Allison,Joshua D. Stender,Hyun B. Chun,David F. Tough,Rab K. Prinjha,Christopher Benner,Christopher K. Glass +10 more
TL;DR: An essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts is suggested.
Journal ArticleDOI
PPARγ and the global map of adipogenesis and beyond
TL;DR: It is now clear that multiple TFs team up to induce PPARγ during adipogenesis, and that other TFs cooperate withPPARγ to ensure adipocyte-specific genomic binding and function.
Journal ArticleDOI
PPARs: Fatty acid sensors controlling metabolism
TL;DR: The function, regulation, and mechanism of the different PPAR subtypes are reviewed with special emphasis on their role in the regulation of lipid metabolism.
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