PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

Lefterova, Martina I.; Zhang, Yong; Steger, David J.; Schupp, Michael; Schug, Jonathan; Cristancho, Ana G.; Feng, Dan; Zhuo, David; Stoeckert, Christian J.; Liu, X. Shirley; Lazar, Mitchell A.

doi:10.1101/gad.1709008

Cited by 732 publications

(764 citation statements)

References 65 publications

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“…Of note, both MED1 clusters coincide with binding peaks for PPARγ and C/EBPβ, two master transcriptional regulators of adipogenesis. 64 Future work will be aimed at validating the functional role of these and other genomic regions in adipogenesis-induced Cd274 / Pd-l1 transcription.…”

Section: Discussionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Section: Discussionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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“…81 Peroxisome proliferator-activated receptor-g (PPAR gamma), CCAAT/enhancer-binding protein (C/EBP) and sterol-regulatory element-binding protein-1 (SREBP-1) are also involved in adipose tissue differentiation and act as transcriptional regulators to modulate gene expression and the functional proteins related to adipose function. [82][83][84][85][86] Some investigators have found that 1,25-dihydroxyvitamin D 3 appears to block adipose tissue differentiation by suppressing LPL, aP2, C/EBP-a, PPAR-g and SREBP-1. 76,77 There is controversy, however.…”

Section: Methodsmentioning

confidence: 99%

The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications

et al. 2011

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Obesity and vitamin D deficiency have both been recognized as major public health issues worldwide, and there is growing evidence that they are related, although the cause-effect relationship remains unclear. Could obesity be contributing to low circulating 25-hydroxyvitamin D concentrations? Alternatively, could low vitamin D status predispose to obesity? In this review, the relationship between low circulating 25-hydroxyvitamin D and obesity, and possible underlying reasons from both perspectives, is presented. One potential mechanism by which obesity could contribute to low serum 25-hydroxyvitamin D is adipose sequestration of vitamin D. On the other hand, adipose tissue has both the vitamin D receptor and the ability to synthesize 1,25-dihydroxyvitamin D, and there is evidence that vitamin D may regulate adipose tissue mass, differentiation and metabolism in ways that might contribute to obesity. Of particular interest, vitamin D deficiency is common both before and after bariatric surgery, and is often difficult to treat, particularly with the more malabsorptive procedures. Additional research is needed to elucidate the complex and multifaceted factors underlying the association between low circulating 25-hydroxyvitamin D and obesity, and to identify optimal treatment approaches in obese individuals and in bariatric surgical patients both before and after surgery.

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“…1C). We chose to study C/EBPα in more detail because it is involved in the activation of differentiation in several cell types (15), including keratinocytes (16)(17)(18) and adipocytes (19)(20)(21), potentially linking C/EBPα binding to methylated promoters with activation of methylated promoters upon differentiation (see below).…”

mentioning

confidence: 99%

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

Rishi

Bhattacharya

Chatterjee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

216

251

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DNA methylation of the cytosine in the CpG dinucleotide is typically associated with gene silencing. Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active, but the mechanism underlying the activation of these methylated promoters remains unclear. Here we show that CpG methylation of the CRE sequence (TGACGTCA) enhances the DNA binding of the C/EBPα transcription factor, a protein critical for activation of differentiation in various cell types. Transfection assays also show that C/EBPα activates the CRE sequence only when it is methylated. The biological significance of this observation was seen in differentiating primary keratinocyte cultures from newborn mice where certain methylated promoters are both bound by C/EBPα and activated upon differentiation. Experimental demethylation by either 5-azacytidine treatment or DNMT1 depletion diminished both C/EBPα binding and activation of the same methylated promoters upon differentiation suggesting that CpG methylation can localize C/EBPα. Transfection studies in cell cultures using methylated tissue-specific proximal promoters identified half-CRE (CGTCA) and half-C/EBP (CGCAA) sequences that need to be methylated for C/EBPα mediated activation. In primary dermal fibroblasts, C/EBPα activates a different set of methylated tissue-specific promoters upon differentiation into adipocytes. These data identify a new function for methyl CpGs: producing DNA binding sites at half-CRE and half-C/EBP sequences for C/EBPα that are needed to activate tissue-specific genes.

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PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

Cited by 732 publications

References 65 publications

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

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