Poly(ADP-Ribose)Polymerase-1 (PARP1) Controls Adipogenic Gene Expression and Adipocyte Function

Abstract

Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was described to affect chromatin compaction. Previous reports suggested a dynamic modulation of the chromatin landscape during adipocyte differentiation. We thus hypothesized that PARP1 plays an important transcriptional role in adipogenesis and metabolism and therefore used adipocyte development and function as a model to elucidate the molecular action of PARP1 in obesity-related diseases. Our results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases during adipocyte development and, at late time points of adipogenesis, is involved in the sustained expression of PPARγ2 and of PPARγ2 target genes. During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks (e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its regulatory function during adipogenesis by altering histone marks. Interestingly, activation of PARP1 enzymatic activity was prevented with a topoisomerase II inhibitor. These data hint at topoisomerase II-dependent, transient, site-specific double-strand DNA breaks as the cause for poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function. Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent gene expression with implications in adipocyte function and obesity-related disease models.

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

“…This or other genetic differences between the SV129 and the C57BL/6J strains that affect metabolic pathways may underlie the observed phenotypic differences. Some of the effects of PARP-1 on adipogenesis are due to direct effects on PPARg-dependent adipogenic gene expression in fat cells (Erener et al 2012), but the system-wide effects of PARP-1 suggest a broad spectrum of functions beyond that.…”

“…As an increasing number of studies have shown, PAR can be accumulated in normal, steady-state, or basal conditions (e.g., during hormonal signaling, certain stages of development, circadian clock function, and mitosis) without triggering stress responses (Tulin and Spradling 2003;Bai et al 2007;Chang et al 2009;Asher et al 2010;Lonn et al 2010;Geistrikh et al 2011;Rouleau et al 2011;Yoo et al 2011;Erener et al 2012). How does the cell interpret PAR accumulation as a stress signal in one circumstance, but not another?…”

Exploring the emerging complexity in transcriptional regulation of energy homeostasis

“…Additional studies using Artd1-knockout mice that were fed a high-fat diet have shown that ARTD1 leads to impaired glucose homeostasis and hepatic lipid deposition 72 . In vitro experiments also showed that ARTD1 controls genes involved in adipogenesis (PPARG) and adipocyte function (aP2 (also known as FABP4) and adiponectin), impairing the differentiation and sustained function of adipocytes 73 . However, a direct link between histone ADP ribosylation and transcriptional regulation has yet to be established.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Thus, the large differences in DNA methylation observed between human preadipocytes and mature adipocytes (Zhu 2012) suggest that epigenetics plays an important role in the process of adipocyte differentiation. Other epigenetic mechanisms that play an important role in adipogenesis are histone methylation and demethylation (Okamura et al, 2010), poly(ADPribosyl)ation (Erener et al, 2012), and acetylation and deacetylation (Kim SJ et al, 2011;Chatterjee et al, 2011). For example, the promoter of the PPARγ gene, a key transcriptional regulator of adipogenesis, is hypermethylated in 3T3-L1 preadipocytes, but is gradually demethylated upon induction of differentiation (Fujiki et al, 2009).…”