XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a

Sun, Yi; Zhang, Yi Xin; Zhang, Dan; Xu, Chen; Chen, Song Chang; Zhang, Jun Yu; Ruan, Ye Chun; Chen, Feng; Zhang, Run Ju; Qian, Ying; Liu, Yi Feng; Jin, Lu; Ma, Tianyu; Xu, Haiyan; Luo, Yu; Liu, Xin Mei; Sun, Fei; Sheng, Jian Zhong; Huang, He

doi:10.1007/s00439-016-1752-9

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…Kitlg has been previously reported to be essential to ovarian development [38] and is an important element in inhibiting apoptosis in different cell types [39]. Our results have shown that BPA downregulates Kitlg expression (Table 5), which may increase the protein level of Bax in offspring mice, suggesting that BPA exposure has inhibitory effects on the development and maturation of oocytes and follicles by interfering with the expressions of Bax and Bcl-2.…”

Section: Discussionsupporting

confidence: 55%

Bisphenol A Exposure during Pregnancy Alters the Mortality and Levels of Reproductive Hormones and Genes in Offspring Mice

Shi

Wang

et al. 2017

BioMed Research International

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The present study investigated the reproductive toxicity of bisphenol A (BPA) exposure to the mother on the offspring mice. BPA was given to pregnant mice at 50 mg/kg, 500 mg/kg, and 2500 mg/kg BW BPA daily by gavage during the whole gestation period. The offspring mice were sacrificed at 8 weeks of age. Results showed that exposure of BPA to the mother increased the mortality (P < 0.05). Maternal exposure of BPA reduced the levels of T (♂) and FSH (♀) (P < 0.01) and elevated E2 (♀) level in the adult offspring (P < 0.01). BPA exposure caused testicular damage as shown by less Leydig cells and ovarian injury as shown by more vacuoles and less corpus granules in the adult offspring mice. Immunohistochemistry revealed that maternal exposure of BPA increased Bax and decreased Bcl-2 at the protein levels in testicular and ovary tissues in the offspring mice. BPA significantly reduced the expression of StAR in male offspring (P < 0.05). Interestingly, the mRNA levels of Cyp11a were significantly decreased in 50 mg/kg groups and were increased in 500 mg/kg group in the males. Reduced Kitlg and elevated Amh at the mRNA levels were detected in the female offspring.

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Section: Discussionsupporting

confidence: 55%

Bisphenol A Exposure during Pregnancy Alters the Mortality and Levels of Reproductive Hormones and Genes in Offspring Mice

Shi

Wang

et al. 2017

BioMed Research International

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“…This further indicated the presence of differently skewed XCI in the proband and her mother, which suggested that clinical heterogeneity resulting from the deletion of the SHOX gene enhancer was caused by the skewed XCI. While SHOX is also an XCI-escaping gene (Carrel and Willard, 2005; Blaschke and Rappold, 2006; Sun et al, 2017). Skewed XCI and escaping XCI are both involved in our case.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous Deletion of the SHOX Gene Enhancer in two Females With Clinical Heterogeneity Associating With Skewed XCI and Escaping XCI

et al. 2019

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Skewed X-chromosome inactivation (XCI) plays an important role in the phenotypic heterogeneity of X-linked disorders. However, the role of skewed XCI in XCI-escaping gene SHOX regulation is unclear. Here, we focused on a heterozygous deletion of SHOX gene enhancer with clinical heterogeneity. Using SNP array, we detected that the female proband with Leri-Weill dyschondrosteosis (LWD) carried an 857 kb deletion on Xp22.3 (encompassing SHOX enhancer) and a 5,707 kb large-fragment deletion on Xq25q26. XCI analysis revealed that the X-chromosome with the Xq25q26 large-fragment deletion was completely inactivated, which forced the complete activation of the other X-chromosome carrying SHOX enhancer deletion. While the Xp22.3 deletion locates on the escaping XCI region, under the combined action of skewed XCI and escaping XCI, transcription of SHOX gene was mainly from the activated X-chromosome with SHOX enhancer defect, involving in the formation of LWD phenotype. Interestingly, this SHOX enhancer deletion was inherited from her healthy mother, who also demonstrated completely skewed XCI. However, the X-chromosome with SHOX enhancer deletion was inactivated, and the normal X-chromosome was activated. Combing with escaping XCI, her phenotype was almost normal. In summary, this study was a rare report of SHOX gene enhancer deletion in a family with clinical heterogeneity due to skewed inactivation of different X-chromosomes, which can help in the genetic counseling and prenatal diagnosis of disorders in females with SHOX defect.

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“…KDM5C encodes a histone lysine demethylase (KDM), and studies have suggested KDMs may act as both oncogenes and tumor suppressors for a variety of cancers (Cloos, Christensen, Agger, & Helin, 2008). KDM5C contributes to ovarian development (Sun et al, 2016), is a candidate tumor suppressor in renal cancer (Dalgliesh et al, 2010), and escape from XCI of KDM5C is also associated with cancer male bias (Dunford et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

An integrative approach to assess X‐chromosome inactivation using allele‐specific expression with applications to epithelial ovarian cancer

Larson

Fogarty

Larson

et al. 2017

Genetic Epidemiology

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X-chromosome inactivation (XCI) epigenetically silences transcription of an X chromosome in females; patterns of XCI are thought to be aberrant in women’s cancers, but are understudied due to statistical challenges. We develop a two-stage statistical framework to assess skewed XCI and evaluate gene-level patterns of XCI for an individual sample by integration of RNA sequence, copy number alteration, and genotype data. Our method relies on allele-specific expression (ASE) to directly measure XCI and does not rely on male samples or paired normal tissue for comparison. We model ASE using a two-component mixture of beta distributions, allowing estimation for a given sample of the degree of skewness (based on a composite likelihood ratio test) and the posterior probability that a given gene escapes XCI (using a Bayesian beta-binomial mixture model). To illustrate the utility of our approach, we applied these methods to data from tumors of ovarian cancer patients. Among 99 patients, 45 tumors were informative for analysis and showed evidence of XCI skewed towards a particular parental chromosome. For 397 X-linked genes, we observed tumor XCI patterns largely consistent with previously identified consensus states based on multiple normal tissue types. However, 37 genes differed in XCI state between ovarian tumors and the consensus state; 17 genes aberrantly escaped XCI in ovarian tumors (including many oncogenes), whereas 20 genes were unexpectedly inactivated in ovarian tumors (including many tumor suppressor genes). These results provide evidence of the importance of XCI in ovarian cancer and demonstrate the utility of our two-stage analysis.

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XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a

Cited by 17 publications

References 36 publications

Bisphenol A Exposure during Pregnancy Alters the Mortality and Levels of Reproductive Hormones and Genes in Offspring Mice

Bisphenol A Exposure during Pregnancy Alters the Mortality and Levels of Reproductive Hormones and Genes in Offspring Mice

Heterozygous Deletion of the SHOX Gene Enhancer in two Females With Clinical Heterogeneity Associating With Skewed XCI and Escaping XCI

An integrative approach to assess X‐chromosome inactivation using allele‐specific expression with applications to epithelial ovarian cancer

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