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

Leung, Karen L.; Sanchita, Smriti; Pham, Catherine T.; Davis, Brett A.; Okhovat, Mariam; Ding, Xiangming; Dumesic, Phillip A.; Grogan, Tristan; Williams, Kevin J.; Morselli, Marco; Ma, Feiyang; Carbone, Lucia; Li, Xinmin; Pellegrini, Matteo; Dumesic, Daniel A.; Chazenbalk, Gregorio D.

doi:10.1186/s13148-020-00970-x

Cited by 18 publications

(12 citation statements)

References 73 publications

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“…However, this variant has been reported to act as an eQTL that modifies the expression FZD5, a Wnt receptor protein, in multiple tissues [80]. Proper Wnt signaling is important for ovarian development and oocyte maturation [81,82] and abnormalities in this pathway have been reported in the endometrium, granulosa cells, and adipose tissue of women with PCOS [83][84][85].…”

Section: Discussionmentioning

confidence: 99%

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Tyrmi

Arffman

Pujol-Gualdo

et al. 2021

Preprint

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Background: Polycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe - Finnish and Estonian - to provide a basis for a new understanding of the genetic determinants of PCOS. Methods and Findings: We conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts. In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 x 10-8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 x 10-16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 x 10-8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16. Conclusions: We identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.

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Section: Discussionmentioning

confidence: 99%

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Tyrmi

Arffman

Pujol-Gualdo

et al. 2021

Preprint

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“…These PCOS subtypes may differ in their developmental origins [ 22 ], with their heritability variably interacting with risk-increasing environmental factors, including maternal obesity and gestational diabetes, to fully explain its prevalence. Such genetic-environmental interactions likely begin before birth, when an altered maternal-placental-fetal environment generates epigenetic modifications in fetal genetic susceptibility to PCOS that continue after birth into adulthood, with metabolic adaptations that enhance fat storage but predispose to lipotoxicity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation

Dumesic

Padmanabhan

Chazenbalk

et al. 2022

Reprod Biol Endocrinol

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As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

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“…However, to our best knowledge, the effects of SFRPs on PCOS have not been reported yet. Considering the fact that SFRP1 was reduced in the subcutaneous abdominal adipose stem cells isolated from patients with polycystic ovarian syndrome [12], this study is the first evidence demonstrating that SFRP1 suppressed granulosa cell proliferation and migration to attenuate PCOS.…”

Section: Discussionmentioning

confidence: 77%

“…SFRP1 has been shown to promote colorectal cancer cell apoptosis and repress cell proliferation and metastasis [10]. SFRP1 suppressed Wnt/β-catenin signaling to inhibit the progression of epithelial ovarian cancer [11], and SFRP1 was reduced in the subcutaneous abdominal adipose stem cells isolated from patients with PCOS [12].…”

Section: Introductionmentioning

confidence: 99%

SFRP1 suppresses granulosa cell proliferation and migration through inhibiting JNK pathway

Zhou¹,

Xia²,

Han³

2021

Clinical and Experimental Obstetrics & Gynecology

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Background: Secreted frizzled-related protein 1 (SFRP1) functions as a Wnt antagonist to repress the proliferation and migration of epithelial ovarian cancer cells. Recent research has shown that SFRP1 was reduced in the subcutaneous abdominal adipose stem cells isolated from patients with polycystic ovarian syndrome (PCOS). Regardless, the regulatory role and mechanism of SFRP1 in the proliferation and migration of granulosa cells during development of PCOS are scarce. Methods: SFRP1 expression was analyzed in plasma samples from patients with PCOS or immortalized human granulosa cells (KGN). Cell counting kit-8 (CCK-8) and colony formation assays were used to analyze the cell viability and proliferation of KGN, respectively. Cell apoptosis was analyzed by flow cytometry, and migration was detected by transwell. Results: SFRP1 expression was lower in plasma samples isolated from patients with PCOS than the healthy control. Immortalized human granulosa cells (KGN) also showed decreased SFRP1 expression compared to normal ovarian epithelial IOSE80 cells. pcDNA-mediated over-expression of SFRP1 reduced the cell viability and proliferation of KGN via cell counting kit-8 (CCK-8) and colony formation assays, respectively. Flow cytometry, analysis showed that the cell apoptosis of KGN was promoted by SFRP1. Ectopic expression of SFRP1 retarded cell migration with down-regulation of MMP2, MMP9, and vimentin. JNK phosphorylation was reduced in KGN with SFRP1 over-expression. Conclusion: SFRP1 contributed to the suppression of granulosa cell proliferation and migration through inhibition of JNK activation, providing a promising molecular target for PCOS.

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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

Cited by 18 publications

References 73 publications

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation

SFRP1 suppresses granulosa cell proliferation and migration through inhibiting JNK pathway

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