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Biochim Biophys Acta Gene Regul Mech. 2018 Jun 30. pii: S1874-9399(18)30095-6. doi: 10.1016/j.bbagrm.2018.06.007. [Epub ahead of print]

Enhancer-driven transcriptional regulation is a potential key determinant for human visceral and subcutaneous adipocytes.

Author information

1
Institute of Biochemistry, Justus-Liebig-University Giessen, Giessen, Germany; Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Marburg, Germany. Electronic address: robert.liefke@imt.uni-marburg.de.
2
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany; Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany.
3
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
4
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany; Department of General and Visceral Surgery, Kreisklinikum Siegen, Siegen, Germany.

Abstract

Obesity is characterized by the excess of body fat leading to impaired health. Abdominal fat is particularly harmful and is associated with cardiovascular and metabolic diseases and cancer. In contrast, subcutaneous fat is generally considered less detrimental. The mechanisms that establish the cellular characteristics of these distinct fat types in humans are not fully understood. Here, we explored whether differences of their gene regulatory mechanisms can be investigated in vitro. For this purpose, we in vitro differentiated human visceral and subcutaneous pre-adipocytes into mature adipocytes and obtained their gene expression profiles and genome-wide H3K4me3, H3K9me3 and H3K27ac patterns. Subsequently, we compared those data with public gene expression data from visceral and subcutaneous fat tissues. We found that the in vitro differentiated adipocytes show significant differences in their transcriptional landscapes, which correlate with biological pathways that are characteristic for visceral and subcutaneous fat tissues, respectively. Unexpectedly, visceral adipocyte enhancers are rich on motifs for transcription factors involved in the Hippo-YAP pathway, cell growth and inflammation, which are not typically associated with adipocyte function. In contrast, enhancers of subcutaneous adipocytes show enrichment of motifs for common adipogenic transcription factors, such as C/EBP, NFI and PPARγ, implicating substantially disparate gene regulatory networks in visceral and subcutaneous adipocytes. Consistent with the role in obesity, predominantly the histone modification pattern of visceral adipocytes is linked to obesity-associated diseases. Thus, this work suggests that the properties of visceral and subcutaneous fat tissues can be studied in vitro and provides preliminary insights into their gene regulatory processes.

KEYWORDS:

Adipocytes; Cancer; Enhancers; Inflammation; Obesity; Transcription factors

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