NCBI Summary:
This gene is located in an imprinted region of chromosome 11 near the insulin-like growth factor 2 (IGF2) gene. This gene is only expressed from the maternally-inherited chromosome, whereas IGF2 is only expressed from the paternally-inherited chromosome. The product of this gene is a long non-coding RNA which functions as a tumor suppressor. Mutations in this gene have been associated with Beckwith-Wiedemann Syndrome and Wilms tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
General function
, Epigenetic modifications
Comment
The relationship between H19 and parameters of ovarian reserve. Xia X et al. (2020) The H19 long noncoding RNA (lncRNA) belongs to a highly conserved, imprinted gene cluster involved in embryonic development and growth control. We previously described a novel mechanism whereby the Anti-mullerian hormone (Amh) appears to be regulated by H19. However, the relationship between circulating H19 and markers of ovarian reserve including AMH not been investigated. To determine whether H19 expression is altered in women with decreased ovarian reserve. Experimental study. Yale School of Medicine (New Haven, USA) and Gazi University School of Medicine (Ankara, Turkey). A total of 141 women undergoing infertility evaluation and treatment. Collection of discarded blood samples and cumulus cells at the time of baseline infertility evaluation and transvaginal oocyte retrieval, respectively. Serum and cumulus cell H19 expression. Women with diminished ovarian reserve (as determined by AMH) had significantly lower serum H19 expression levels as compared to controls (p < 0.01). Serum H19 was moderately positively correlated with serum AMH. H19 expression was increased 3.7-fold in cumulus cells of IVF patients who demonstrated a high response to gonadotropins, compared to low responders (p < 0.05). In this study, we show that downregulation of H19 in serum and cumulus cells is closely associated with decreased ovarian reserve, as measured by decreased AMH levels and reduced oocyte yield at oocyte retrieval. Further study with expanded sample sizes is necessary to determine whether H19 may be of use as a novel biomarker for diminished ovarian reserve.//////////////////Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes. Ibala-Romdhane S et al. ART is suspected to generate increased imprinting errors in the lineage. Following an intra cytoplasmic sperm injection (ICSI) procedure, a certain number of embryos fail to develop normally and imprinting disorders may be associated to the developmental failure. To evaluate this hypothesis, we analysed the methylation profile of H19DMR, a paternally imprinting control region, in high-graded blastocysts, in embryos showing developmental anomalies, in the matching sperm and in oocytes of the concerned couples when they were available. Significant hypomethylation of the paternal allele was observed in half of the embryos, independently of the stage at which they were arrested (morula, compacted morula, pre blastocyst or BC-graded blastocysts). Conversely, some embryos showed significant methylation on the maternal allele, whereas few others showed both hypomethylation of the paternal allele and abnormal methylation of the maternal allele. The matching sperm at the origin of the embryos exhibited normal methylated H19 patterns. Thus, hypomethylation of the paternal allele in the embryos does not seem inherited from the sperm but likely reflects instability of the imprint during the demethylating process, which occurred in the early embryo. Analysis of a few oocytes suggests that the defect in erasure of the paternal imprint in the maternal germ line may be responsible for the residual methylation of the maternal allele in some embryos. None of these imprinting alterations could be related to a particular stage of developmental arrest; compared with high-grade blastocysts, embryos with developmental failure are more likely to have abnormal imprinting at H19 (P<0.05).European Journal of Human Genetics advance online publication, 8 June 2011; doi:10.1038/ejhg.2011.99.
Cellular localization
Comment
candidate123
Ovarian function
Initiation of primordial follicle growth, Preantral follicle growth, Early embryo development
Comment
H19ICR methylation requires an imprinted environment only in the male germ line. Gebert C et al. The 2.4 kb H19 imprinting control region (H19ICR) is required to establish parent-of-origin specific epigenetic marks and expression patterns at the Igf2/H19 locus. H19ICR activity is regulated by DNA methylation. The ICR is methylated in sperm but not in oocytes and this paternal specific methylation is maintained throughout development. We recently showed that the H19ICR can work as an ICR even when inserted into the normally non-imprinted alpha fetoprotein locus. Paternal but not maternal copies of the ICR become methylated in somatic tissue. However, the ectopic ICR remains unmethylated in sperm. To extend these findings and investigate the mechanisms that lead to methylation of the H19ICR in the male germ line, we characterized novel mouse knock-in lines. Our data confirm that the 2.4 kb element is an autonomously acting ICR whose function is not dependent on germ line methylation. Ectopic ICRs become methylated in the male germ line, but the timing of methylation is influenced by the insertion site and by additional genetic information. Our results support the idea that DNA methylation is not the primary genomic imprint and that the H19ICR insertion is sufficient to transmit parent-of-origin dependent DNA methylation patterns independent of its methylation status in sperm.
Loss of Methylation at H19 DMD Is Associated with Biallelic Expression and Reduced Development in Cattle Derived by Somatic Cell Nuclear Transfer. Suzuki J et al. Although cloning of mammals has been achieved successfully, the percentage of live offspring is very low due to reduced fetal size, and fewer implantation sites. Recent studies have attributed such pathological conditions to abnormal reprogramming of the donor cell used for cloning. The inability of the oocyte to fully restore the differentiated status of a somatic cell to its pluripotent and undifferentiated state is normally evidenced by aberrant DNA methylation patterns established throughout the genome during development to blastocyst. These aberrant methylation patterns are associated with abnormal expression of imprinted genes, which among other genes, are essential for normal embryo development and gestation. We hypothesized that embryo loss and low implantation rates in cattle derived by somatic cell nuclear transfer (SCNT) are caused by abnormal epigenetic reprogramming of imprinted genes. To verify our hypothesis, we analyzed the parental expression and the differentially methylated domain (DMD) methylation status of the H19 gene. Using a parental-specific analysis, we confirmed for the first time that H19 biallelic expression is tightly associated with a severe demethylation of the paternal H19 DMD in SCNT embryos, suggesting that these epigenetic anomalies to the H19 locus could be directly responsible for the reduced size and low implantation rates of cloned embryos in cattle.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
The expression profile of the H19 gene in cattle. Khatib H et al. The expression of the H19 gene has been well studied in fetal human and mouse tissues but not in cattle. It is generally believed that H19 is abundantly expressed in the early stages of embryogenesis and is repressed postnatally. We report the expression pattern of this gene in cattle in a total of 120 fetal-organ combinations and in a total of 108 adult-organ combinations using quantitative real time PCR. In fetal tissues, H19 was abundantly expressed in amnion, chorion, and allantois. Fetal liver, lung, heart, spleen, eye, rib, mammary gland, and cotyledon showed moderate expression, while intestine and brain showed lower expression levels. For some organs examined in this study, the expression pattern in cattle fetal organs was similar to that of human, mouse, and sheep. For adult organs, H19 was highly expressed in muscle and moderately expressed in liver, lung, heart, kidney, pancreas, and ovary. Low expression levels were observed for adult spleen, caruncle, and endometrium. Of considerable interest was the observation that H19 transcripts have not been detected in the mouse and human kidney or in the mouse spleen. In contrast, we observed significant expression levels in adult kidney and low expression levels in adult spleen. In a comparison of adults and fetuses, significant differences in H19 expression levels were found for liver, lung, heart, and spleen. The expression pattern in adults implies that, in addition to possible roles in embryogenesis, the H19 gene may have other functions.
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: A novel, noncoding-RNA-mediated, post-transcriptional mechanism of AMH regulation by the H19/let-7 axis. Qin C et al. (2018) In reproductive age women, the pool of primordial follicles is continuously depleted through the process of cyclic recruitment. AMH both inhibits the initial recruitment of primordial follicles into the growing pool and modulates the sensitivity of growing follicles to FSH. Thus, AMH may be an important modulator of female infertility and ovarian reserve; however, the mechanisms regulating AMH remain unclear.To evaluate AMH levels in the absence of H19 lncRNA, H19 knockout (H19KO) mice were evaluated for analysis of ovarian AMH gene expression, protein production, and reproductive function, including assessment of follicle numbers and litter size analysis. To further investigate regulation of AMH by the H19/let-7 axis, let-7 binding sites on AMH were predicted, and in vitro studies of the effect of H19 knockdown/overexpression with let-7 rescue were performed. Lastly, response to superovulation was assessed via oocyte counts and estradiol measurements.The H19KO mouse demonstrates subfertility and accelerated follicular recruitment with increased spontaneous development of secondary, preantral and antral follicles. Ovaries of H19KO mice have decreased AMH mRNA and protein, and AMH mRNA has a functional let-7 binding site, suggesting a plausible ncRNA-mediated mechanism for AMH regulation by H19/let-7. Lastly, in the absence of H19, superovulation results in higher estradiol and more oocytes, suggesting that H19 functions to limit the number of follicles that mature, produce estradiol, and ovulate. Thus, AMH's inhibitory actions are regulated at least in part by H19, likely via let-7, marking this ncRNA pair as important regulators of the establishment and maintenance of the follicular pool.//////////////////
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: Long non-coding RNA H19 is associated with polycystic ovary syndrome in Chinese women: a preliminary study. Qin L et al. (2019) Polycystic ovary syndrome (PCOS) represents a serious reproductive and endocrine condition and is associated with high incidence rates. H19 is a compelling long noncoding RNA (lncRNA) which carries out a range of biological functions. However, prior to this study, little was known as to whether there was an association between lncRNA H19 and PCOS. In the current study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to determine lncRNA H19 expression levels in peripheral blood leukocytes from patients with PCOS and compared this data with that derived from normal controls. We also screened data for potential relationships between lncRNA H19 and a range of endocrine variables in PCOS. The expression of lncRNA H19 was significantly higher in cases of PCOS than in controls. Individuals exhibiting higher expression levels of lncRNA H19 were associated with a significantly higher risk of PCOS than those with lower expression levels. Moreover, lncRNA H19 expression was positively correlated with fasting plasma glucose levels; this was the case with both raw data, and after adjustment for age and BMI in the PCOS group. However, lncRNA H19 expression showed no significant correlation with total testosterone or insulin resistance in either PCOS cases or the controls. In conclusion, we demonstrate the first evidence to indicate that lncRNA H19 is associated with PCOS, suggesting that elevated lncRNA H19 levels are a risk factor for PCOS. For susceptible individuals, lncRNA H19 may represent a useful biomarker of the early stages of endocrine and metabolic disorders in PCOS.//////////////////