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Cell-Specific Determinants of PPARg Function in Adipocytes and Macrophages

ABSTRACT: The nuclear receptor Peroxisome Proliferator Activator Receptor (PPAR ) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side-effects that limit widespread use. PPAR is required for adipocyte differentiation, but is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPAR binding in macrophages occurs at the same or different genomic locations compared to adipocytes. Here, utilizing chromatin immunoprecipitation and high throughput sequencing (ChIP-seq), we demonstrate that PPAR cistromes in adipocytes and macrophages are predominantly cell type specific. In macrophages, PPAR 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. PPAR , when introduced into cells that are neither macrophages nor adipocytes, 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 PPAR function is regulated by cell-specific chromatin accessibility, histone marks, and transcription factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE21314 | GEO | 2010/04/14

SECONDARY ACCESSION(S): PRJNA126321

REPOSITORIES: GEO

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Project description:Full title: Complex patterns of genome accessibility discriminate sites of PcG repression, H4K16 acetylation and replication initiation Histone modifications have been proposed to regulate gene expression in part by modulating DNA accessibility and higher-order chromatin structure. However, there is limited direct evidence to support structural differences between euchromatic and heterochromatic fibers in the nucleus. To ask how histone modifications relate to chromatin compaction, we measured DNA accessibility throughout the genome by combining M.SssI methylase footprinting with methylated DNA immunoprecipitation (MeDIP-footprint). In the Drosophila genome, we find that accessibility to DNA methylase is variable in a manner that relates to the differential distribution of active and repressive histone modifications. Active promoters are highly permissive to M.SssI activity, yet inactive chromosomal domains decorated with H3 lysine 27 trimethylation are least accessible providing in vivo evidence for Polycomb-mediated chromatin compaction. Conversely, DNA accessibility is increased at active chromosomal regions marked with H4 lysine 16 acetylation and at the dosage-compensated male X chromosome suggesting that Drosophila transcriptional dosage compensation is facilitated by more permissive chromatin structure. Interestingly early replicating chromosomal regions and sites of replication initiation show also higher accessibility linking temporal and spatial control of genome duplication to the structural organization of chromatin. In conclusion, using a novel protocol we generated a comprehensive view of DNA accessibility and uncover different levels of chromatin organization, which are delineated by distinct patterns of posttranslational histone modifications and replication. Keywords: cell type comparison, ChIP-chip, MeDIP-footprint, RNA-seq, ChIP-seq MeDIP-footprint and ChIP-chip: ChIP-chip was performed for H3K4me3, H3K36me2, H3K36me3, H3K27me3, and H3K9me2 in Kc cells. We measured DNA accessibility throughout the genome by combining M.SssI methylase footprinting with methylated DNA immunoprecipitation (MeDIP-footprint) in Kc and S2 cells. RNA-seq: cDNA from RNA from Drosophila Kc cells was sequenced using Illumina deep sequencing. Reads were mapped and the abundance of all transcripts was determined. ChIP-seq: PSC ChIP from Drosophila Kc cells was sequenced using Illumina deep sequencing in three lanes. Reads were mapped and the binding profile of PSC was determined.

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Cell-Specific Determinants of PPARg Function in Adipocytes and Macrophages

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