HDAC4 regulates the proliferation, migration, and invasion of trophoblasts in pre-eclampsia through the miR-134-5p/FOXM1 axis.

Epigenetics, including histone modifications and noncoding RNAs, affects abnormal placental function in pre-eclampsia (PE). This study was conducted to explore the role of histone deacetylase 4 (HDAC4) in trophoblast invasion and migration. The expression levels of HDAC4, microRNA (miR)-134-5p, and forkhead box protein M1 (FOXM1) in placentas from PE patients and healthy controls and their correlations were examined. HTR8/SVneo cells were cultured and underwent gene intervention. Then, trophoblast proliferation, invasion, and migration were evaluated by 5-ethynyl-2'deoxyuridine, Transwell, and scratch assays. The enrichments of HDAC4 and acetylated histone H3 at lysine 9 (H3K9Ac) on the miR-134-5p promoter were quantified by chromatin immunoprecipitation. The binding of miR-134-5p to FOXM1 was analyzed by dual-luciferase assay. HDAC4 and FOXM1 were downregulated while miR-134-5p was upregulated in PE placentas. HDAC4 downregulation impaired trophoblast proliferation, invasion, and migration while HDAC4 overexpression played the opposite role. Mechanically, HDAC4 deacetylated H3K9Ac to repress miR-134-5p expression by erasing H3K9Ac, reduced the binding of miR-134-5p to FOXM1, and then promoted FOXM1 transcription. miR-134-5p overexpression or FOXM1 downregulation abrogated the promotive role of HDAC overexpression in trophoblast invasion and migration. Our study unraveled a novel mechanism of trophoblast proliferation, invasion, and migration and proposed that HDAC4 may be a promising target for the treatment of PE.

LncRNA XIST promotes insulin resistance in gestational diabetes mellitus via the microRNA-181b-5p/NDRG2 axis.

Many studies have explored the role of lncRNA X inactivation-specific transcript (XIST) in diabetes. This study was designed to unravel the regulatory mechanism of XIST on animal models of gestational diabetes mellitus (GDM) progression via the microRNA (miR)-181b-5p/N-myc downstream-regulated gene 2 (NDRG2) axis. XIST, miR-181b-5p, and NDRG2 expression levels in GDM mice were detected. The GDM mice were subjected to gain- and loss-of-function assays to examine the change of glucose metabolism indices (fasting blood glucose (FBG), fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR)), serum oxidative stress factors (glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA)), serum inflammatory factors (interleukin-1 ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α)), pathological changes of pancreatic tissues, and apoptotic cells in pancreatic islets in GDM mice. XIST and NDRG2 expression were elevated while miR-181b-5p expression was depleted in GDM mice. Down-regulated XIST or NDRG2 or up-regulated miR-181b-5p reduced the FBG level, HOMA-IR, and serum IL-1ß, IL-6, and TNF-α, and MDA contents, elevated the FINS, GSH, and SOD level, mitigated pathological changes in pancreatic tissues, and decelerated apoptotic cells in pancreatic islets in GDM mice. Silenced XIST dampens insulin resistance in GDM mice via the modulation of the miR-181b-5p/NDRG2 axis.

CYP17A1 mutations identified in 17 Chinese patients with 17α-hydroxylase/17,20-lyase deficiency.

CONTEXT: 17α-hydroxylase deficiency (17OHD) is a relatively rare disease, accounting for about 1% of congenital adrenal hyperplasia cases. The CYP17A1 gene mutation can lead to this disease. Human CYP17A1 gene is located on chromosome 10q24.3. It consists of eight exons encoding 508 amino acids. To date, more than 50 mutations in exons and introns of the CYP17A1 gene have been reported to cause complete or partial 17OHD. OBJECTIVE: The aim of this study was to investigate the CYP17A1 gene mutation types in 17 Chinese patients, containing 11 complete and six partial 17OHD patients. SETTING: We conducted the study in the Department of Obstetrics and Gynecology of Peking Union Medical College Hospital. PATIENTS: Seventeen patients were studied with complete or partial 17OHD. MAIN OUTCOME MEASURES: The CYP17A1 gene was sequenced and we measured steroid and sex hormone levels. RESULTS: Analysis of the CYP17A1 gene in our patients revealed 12 different kinds of mutation. Two mutations (IVS1-1G>A and L209P) were novel mutations. Mutation c.985_987delTACinsAA (Y329KfsX418) in Exon 6 was the most common mutation in Chinese patients, accounting for 50 percents of the mutant alleles (17/34). Exon 6 was the hot spot since most mutations were detected in this exon (59%, 20/34 alleles). There was no mutation detected in the Exons 4 and 5.

[Clinical study on 48 cases with complete 17α-hydroxylase deficiency].

OBJECTIVE: To investigate efficient diagnosis and treatment of 17α-hydroxylase (17OHD) deficiency by summarizing clinical characteristics of those patients. METHODS: From January 1983 to January 2010, 48 cases with 17OHD in Peking Union Medical College Hospital were studied retrospectively. RESULTS: Among 48 patients with 17OHD, karyotype analysis showed, 12 cases with 46, XX and 36 cases with 46, XY. The 46, XX karyotype and 46, XY karyotype with complete 17OHD had typical clinical presentation of amenorrhea[12/12, 100% (36/36)], no typical spontaneous puberty [12/12, 13.9% (5/36)], Hypertension [11/12, 100% (36/36)], hypokalemia [K(+): (2.6 ± 0.7), (2.8 ± 0.7) mmol/L], hypergonadotropin [follicle-stimulatinghormone (FSH): (51 ± 35), (79 ± 46) U/L, luteinizing hormone (LH): (27 ± 14), (49 ± 37) U/L], impaired production of sex hormones [testosterone (T): 0.003, 0.005 nmol/L; estradiol (E(2)): 26.86, 10.64 pmol/L], hyper-progesterone[ (P): (32 ± 15), (29 ± 23) nmol/L], impaired production of 17α-hydroxyprogesterone (17α-OHP)[(2.5 ± 1.1), (2.4 ± 1.7) nmol/L], ACTH hypersecreation (91.8, 114.0 pmol/L). ACTH stimulating test did not elevated in 17α-OHP and cortisol. CONCLUSION: When patients with elevated basal serum levels of progesterone higher than that of ovulation period in addition to clinical symptoms, examination about 17OHD should be warranted.