Methylome and transcriptome profiling revealed epigenetic silencing of LPCAT1 and PCYT1A associated with lipidome alterations in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine diseases of fertile women and a major cause of infertility. The regulatory effects of DNA methylation on gene transcription and downstream lipid metabolism have not been explored in PCOS. In this study, MBD-seq and RNA-seq were performed on ovarian granulosa cells of PCOS patients and controls, and methylation specific PCR and quantitative polymerase chain reaction were used to validate the results. Then lipidomic profiling was conducted on serum of PCOS patients and controls using UPLC-MS. We identified 73 genes with differently methylated promoters and 830 differently expressed genes. The promoter regions of LPCAT1 and PCYT1A were hypermethylated, accompanied by downregulation of their messenger RNA expression, which may be involved in the regulation of PCOS through downstream glycerophospholipid metabolism and phosphatidylcholine synthesis. The lipid profiling results showed significant changes in 21 lipids, which demonstrated the disturbance in glycerophospholipid metabolism and glycerolipid metabolism pathways. Furthermore, the metabolites-genes interaction network was constructed to illustrate the association of aberrant methylome and transcriptome with lipidome alterations in glycerolipid and glycerophospholipid metabolism pathways. Our study suggested that the methylation silencing of LPCAT1 and PCYT1A may promote glycerophospholipids metabolism dysregulation, which provided a novel genetic and lipometabolic basis for the pathogenesis of PCOS.

The Combined Use of Copper Sulfate and Trichlorfon Exerts Stronger Toxicity on the Liver of Zebrafish

“…Glycerophospholipids are the most abundant phospholipids in the human body and are involved in membrane protein recognition and signal transduction, and are associated with various metabolic diseases, such as cardiovascular diseases, hypertension, diabetes, obesity, nervous system diseases, etc. [ 34 , 35 ]. One key difference between copper sulfate and Tri is that Cu 2+ accumulates in tissues [ 36 ], which means that the concentration of Cu 2+ in zebrafish increases after each water change.…”

Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis

“…[ 28 , 29 ] We find LPCAT1 is under direct control of NRF1, thus provide the evidence of transcriptional regulation of LPCAT1 for the first time. We did not analyze lipidomic change by mass spectrometry upon silencing NRF1 in our investigation, but considering the unequivocal regulation of NRF1 on LPCAT1 transcription and the explicit effect of LPCAT1 on PC metabolism,[ 16 , 30 , 31 ] we believe NRF1 could alter phospholipid metabolism in HCC.…”

Identification of the hub genes in polycystic ovary syndrome based on disease‐associated molecule network

“…Wang et al identified molecular mechanisms and the novel therapeutic target of late‐onset Alzheimer's disease based on integrating the whole genome and transcriptome 20 . By combining transcriptome and methylome analysis, Zhao et al identify many new ceRNA axes in granulosa cells were associated PCOS, 21 and Mao et al revealed epigenetic silencing of LPCAT1 and PCYT1A associated with lipidome alterations in PCOS 22 …”

“…20 By combining transcriptome and methylome analysis, Zhao et al identify many new ceRNA axes in granulosa cells were associated PCOS, 21 and Mao et al revealed epigenetic silencing of LPCAT1 and PCYT1A associated with lipidome alterations in PCOS. 22 Given the genetic and metabolic characteristics of PCOS, it is essential to systematically integrate gene/ protein (indicating both genetic regulation and environment) 18 and metabolites (reflecting phenotype under the regulation of gene/protein) analysis to reveal new PCOSassociated signatures. 23 Recently, some multi-omics studies of combining transcriptomic and metabolomic have identified differentially expressed molecular signatures in whole blood and follicular fluid to investigate the regulatory mechanism of PCOS.…”