Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming

Autor: Daniel A. Dumesic, Lucia Carbone, Mariam Okhovat, Phillip A. Dumesic, Catherine T. Pham, Feiyang Ma, Xiangming Ding, Xin-Min Li, Marco Morselli, Matteo Pellegrini, Gregorio D. Chazenbalk, Tristan Grogan, Kevin J. Williams, Smriti Sanchita, Brett Davis, Karen L. Leung
Rok vydání: 2020
Předmět:
Epigenomics
Adipose tissue
Gene Expression
Body Mass Index
chemistry.chemical_compound
Stem Cell Research - Nonembryonic - Human
Adipocyte
Gene expression
Adipocytes
Wnt Signaling Pathway
Genetics (clinical)
Polycystic ovary syndrome
Chromatin accessibility
Adipogenesis
Stem Cells
Fatty Acids
Total content
Cell Differentiation
Polycystic ovary
Chromatin
Female
Stem Cell Research - Nonembryonic - Non-Human
Adult
Fat storage
medicine.medical_specialty
1.1 Normal biological development and functioning
Clinical Sciences
Subcutaneous Fat
Biology
Chromatin remodeling
Transforming Growth Factor beta1
Paediatrics and Reproductive Medicine
Lipid oxidation
Clinical Research
Underpinning research
Internal medicine
medicine
Genetics
Humans
De novo synthesis of fatty acids
Obesity
Molecular Biology
Research
Lipid Metabolism
Stem Cell Research
Adipose stem cells
Endocrinology
Cellular programming
chemistry
Case-Control Studies
Transcriptional factors
RNA
Developmental Biology
Zdroj: Clinical epigenetics, vol 12, iss 1
Clinical Epigenetics
Popis: Background Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. Results SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. Conclusions In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.
Databáze: OpenAIRE
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