Imprinting: silently crossing the boundary.
Recent studies have identified silencers as control elements that may interact with enhancers to regulate the expression of imprinted genes.
Animals↗
SEARCH · PubMed Health
Results for “noncoding RNA”
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Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint.
BACKGROUND: The progression to critical COVID-19 arises predominantly from a dysregulated host immune response although the underlying regulatory mechanisms still remain partially elusive. This limits a prompt prediction of the disease progression, reduces the therapeutic options and restrains our understanding of “long COVID”. METHODS: Here, we analyzed the transcriptome of peripheral blood mononuclear cells (PBMCs) collected from COVID-19 patients experiencing different degrees of the disease (mild and critical), and control patients enrolled in the clinical trial COntAGIouS as well as independent bulk RNA-seq, single-cell RNA-seq and proteomic datasets. RESULTS: In critical COVID-19 patients, the integrative analysis of transcriptomic data revealed an altered regulatory network involving microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and coding genes that control mRNA translation-related genes, epigenetics, and metabolism. In parallel, we observed an upregulation of tRNA aminoacylation genes in critical COVID-19 patients by the analysis of either bulk or single-cell RNA-seq data from publicly available independent cohorts. Additionally, we found increased expression of coding genes enriched for the cognate amino acids (glycine, alanine, isoleucine and tyrosine), all related to protein localization, post-translational modifications, and cell metabolism in our cohort. Similar alterations in amino acid frequency were found in an independent proteomic dataset. CONCLUSIONS: Collectively, our findings indicate a broad perturbation of the gene expression landscape that characterizes the aberrant host immune response in critical COVID-19 patients and is potentially coordinated by miRNA and tRNA metabolism alterations. TRIAL REGISTRATION: COntAGIouS, NCT04327570. Registered 26 March 2020, https://clinicaltrials.gov/ct2/show/NCT04327570 .
Female↗
CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues.
The adjacent IGF2 and H19 genes are imprinted in most normal mouse and human tissues, but imprinting is often lost in tumors. Mouse models suggest that parental-allele specific CCCTC-binding factor (CTCF) binding at the IGF2/H19 imprinting control region (ICR) regulates the expression of these two genes. Using chromatin immunoprecipitation and PCR, we show that in several normal and neoplastic human tissues, CTCF consistently binds unmethylated ICR elements, but CTCF binding does not result in predictable gene expression. In the fetal brain, CTCF binding is monoallelic and specific for the unmethylated ICR, yet IGF2/H19 expression is biallelic. In osteosarcoma tumors, aberrant methylation of the IGF2/H19 ICR results in equally aberrant CTCF binding, yet expression of these genes does not correlate with CTCF binding. This is the first description of chromatin immunoprecipitation for CTCF binding at the human IGF2/H19 ICR, and the results demonstrate that CTCF binding at the IGF2/H19 ICR is insufficient to regulate the expression of IGF2/H19 in many human tissues.
Alleles↗
Imprinting and expression of insulin-like growth factor-II and H19 in normal breast tissue and breast tumor.
Insulin-like growth factor (IGF)-II is a mitogenic peptide that has been reported to play an important role in the formation and growth of a variety of tumors. In most tissues, the IGF-II gene (IGF2) is parentally imprinted, with only the paternal allele being expressed. IGF2 messenger RNA (mRNA) and protein are overexpressed in some benign and malignant tumors. H19, a tumor suppressor gene located directly downstream from IGF2, is also genomically imprinted, but the paternal allele is silenced. It has been suggested that alterations in the imprinting of these two genes, which are located at chromosome 11p15.5, may lead to a malignant diathesis. We examined 18 fresh-frozen (FF) breast tumors with their adjacent normal breast tissue and 14 sets of paraffin-embedded formalin-fixed tissues for IGF2 and H19 gene expression and imprinting. IGF2 mRNA and H19 RNA could be quantitated in 15 of the 18 FF tumors. Although three of these tumors showed a > or = 2-fold increase in IGF2 expression when compared with the normal control tissues, the average abundance of IGF2 mRNA in 8 of 15 FF samples was < 50% that observed in the normal tissue. The expression of H19 RNA in these tumors was increased by > or = 2-fold in 5 tumors, but decreased by < or = 50% in 6 tumors when compared with normal adjacent tissue. By examining the ApaI and CA-repeat polymorphisms in the IGF2 gene, we found that the imprinting of IGF2 was maintained in all but 2 of the 17 informative subjects. H19 imprinting was maintained in all 18 informative fresh-frozen and paraffin-embedded formalin-fixed samples. Our data suggest that alterations in IGF2 and H19 gene expression and loss of imprinting do not occur reliably in breast cancer.
Alleles↗
Characterization of monoclonal antibodies specific for the human growth hormone 22K and 20K isoforms.
We have derived and characterized a set of monoclonal antibodies (mAb) specific for the different human GH (hGH) isoforms. The binding characteristics of each antibody to the hGH isoforms (22K and 20K) were analyzed in direct and competitive immunoassays as well as by Western blot. We studied the effects of these mAb on the biological activity of hGH and showed that they specifically block their respective activities. Using these mAb, we developed several immunoassays that have been applied for the quantitation of the different hGH isoforms in body fluids. Therefore, these mAb may help to unravel the biological function of these variants.
Animals↗
Ribonucleic acid expression of the clustered imprinted genes, p57KIP2, insulin-like growth factor II, and H19, in adrenal tumors and cultured adrenal cells.
The recently cloned cyclin-dependent kinase inhibitor gene p57KIP2 is genomically imprinted and located on human chromosome 11p15.5. This region contains two other imprinted genes, insulin-like growth factor II (IGF-II) and H19, both of which seem to be implicated in adrenal neoplasms. We analyzed the expression of the putative tumor suppressor p57KIP2 gene by Northern blotting in normal and hyperplastic adrenals, adrenocortical tumors, and pheochromocytomas. The expression of p57KIP2 messenger ribonucleic acid (mRNA) correlated positively with H19 and negatively with IGF-II RNA in adrenocortical tissues. p57KIP2 mRNA (and H19 RNA) was abundantly expressed in normal human adrenals, adrenocortical adenomas from patients with Cushing's or Conn's syndrome or without clinical evidence of hormone overproduction, hyperplastic adrenals, and tumor-adjacent adrenal tissues, in which IGF-II mRNA expression was low. In most adrenocortical carcinomas and virilizing adrenal adenomas, very low levels of both p57KIP2 and H19 RNAs were observed, whereas IGF-II was highly expressed. In pheochromocytomas, p57KIP2 and H19 RNA expression was highly variable, but on the average it was about 45% and 27%, respectively, of that in normal and tumor-adjacent adrenals. In cultured adrenocortical cells, ACTH and dibutyryl cAMP treatment slightly reduced the predominant 1.7-kilobase (kb) transcript of p57KIP2 gene, but induced a 2.5-kb transcript with a simultaneous increase in H19 RNA expression. The stimulatory effect of ACTH on the 2.5-kb p57KIP2 and H19 transcript accumulation was enhanced by exogenous IGF-II and IGF-I. Our data show that p57KIP2 and H19 RNAs are expressed usually in parallel in normal and pathological adrenocortical tissues. The decreased expression of both p57KIP2 and H19 RNAs in conjunction with elevated IGF-II mRNA expression in hormonally active adrenocortical carcinomas suggests that the loss of expression of the putative tumor suppressor genes p57KIP2 and H19 may be involved in the pathogenesis of these neoplasms.
Adrenal Gland Neoplasms↗
Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression.
It has been previously shown that adrenocortical tumors (ACT) in adults exhibit structural abnormalities in tumor DNA in approximately 30% of cases. These abnormalities involve chromosome 11p15 and include loss of heterozygosity, paternal isodisomy, and overexpression of the gene for insulin-like growth factor II (IGF2), correlating with DNA demethylation at this locus. It has been hypothesized that these events occur late in the tumorigenic process in adults and seem to correlate with a worse prognosis. We present 4 pediatric cases of ACT diagnosed at 2.5 yr, 10 months, 12 yr, and 2.2 yr. All 4 patients presented with virilization, and 1 patient also showed signs and symptoms of glucocorticoid excess. The youngest patient's maternal aunt had surgical excision of a more than 15-cm ACT 18 yr previously, but the aunt is doing well at age 23 yr. They all had surgical removal of their tumors. The 2.5-yr-old child also received chemotherapy and radiotherapy because of capsular rupture and, after 3 local recurrences, died 3.3 yr after initial presentation. We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis. All 4 tumors (100%) showed a combination of structural abnormalities at the 11p15 locus with mosaic loss of heterozygosity involving 11p. All tumors also had significantly increased IGF2 messenger ribonucleic acid levels relative to normal adrenal (up to 36-fold) and significant IGF2 demethylation (mean, 87%). H19 messenger ribonucleic acid levels were undetectable in 3 of 4 tumors, explained in part by mosaic loss of the actively expressed maternal allele for this imprinted gene. By immunohistochemistry we were able to confirm increased IGF-II peptide levels within the tumor tissue in 10 pediatric patients, including the 4 patients described above. Concomitantly, we also observed nuclear accumulation of p53, suggesting somatic mutations. For the 10-month-old patient, sequencing revealed a p53 germline mutation. We therefore conclude that in pediatric ACT, structural abnormalities of tumor DNA and IGF2 overexpression as well as p53 mutations are very common and are therefore less useful for prognosis than in adults. Our findings support the theory that pediatric ACT, whose IGF2 expression and steroidogenesis evoke the phenotype of the fetal adrenal cortex, may arise because of defective apoptosis.
Adrenal Cortex Neoplasms↗
Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors.
Low H19 and abundant IGF-II expression may have a role in the development of adrenocortical carcinomas. In the mouse, the H19 promoter area has been found to be methylated when transcription of the H19 gene is silent and unmethylated when it is active. We used PCR-based methylation analysis and bisulfite genomic sequencing to study the cytosine methylation status of the H19 promoter region in 16 normal adrenals and 30 pathological adrenocortical samples. PCR-based analysis showed higher methylation status at three HpaII-cutting CpG sites of the H19 promoter in adrenocortical carcinomas and in a virilizing adenoma than in their adjacent normal adrenal tissues. Bisulfite genomic sequencing revealed a significantly higher mean degree of methylation at each of 12 CpG sites of the H19 promoter in adrenocortical carcinomas than in normal adrenals (P < 0.01 for all sites) or adrenocortical adenomas (P < 0.01, except P < 0.05 for site 12 and P > 0.05 for site 11). The mean methylation degree of the 12 CpG sites was significantly higher in the adrenocortical carcinomas (mean +/- SE, 76 +/- 7%) than in normal adrenals (41 +/- 2%) or adrenocortical adenomas (45 +/- 3%; both P < 0.005). RNA analysis indicated that the adrenocortical carcinomas expressed less H19 but more IGF-II RNAs than normal adrenal tissues did. The mean methylation degree of the 12 H19 promoter CpG sites correlated negatively with H19 RNA levels (r = -0.550; P < 0.01), but positively with IGF-II mRNA levels (r = 0.805; P < 0.001). In the adrenocortical carcinoma cell line NCI-H295R, abundant IGF-II, but minimal H19, RNA expression was detected by Northern blotting. Treatment with a cytosine methylation inhibitor, 5-aza-2'-deoxycytidine, increased H19 RNA expression, whereas it decreased IGF-II mRNA accumulation dose- and time-dependently (both P < 0.005) and reduced cell proliferation to 10% in 7 d. Our results suggest that altered DNA methylation of the H19 promoter is involved in the abnormal expression of both H19 and IGF-II genes in human adrenocortical carcinomas.
Adenoma↗
Pus3p- and Pus1p-dependent pseudouridylation of steroid receptor RNA activator controls a functional switch that regulates nuclear receptor signaling.
It was previously shown that mouse Pus1p (mPus1p), a pseudouridine synthase (PUS) known to modify certain transfer RNAs (tRNAs), can also bind with nuclear receptors (NRs) and function as a coactivator through pseudouridylation and likely activation of an RNA coactivator called steroid receptor RNA activator (SRA). Use of cell extract devoid of human Pus1p activity derived from patients with mitochondrial myopathy and sideroblastic anemia, however, still showed SRA-modifying activity suggesting that other PUS(s) can also target this coactivator. Here, we show that related mPus3p, which has a different tRNA specificity than mPus1p, also serves as a NR coactivator. However, in contrast to mPus1p, it does not stimulate sex steroid receptor activity, which is likely due to lack of binding to this class of NRs. As expected from their tRNA activities, in vitro pseudouridylation assays show that mPus3p and mPus1p modify different positions in SRA, although some may be commonly targeted. Interestingly, the order in which these enzymes modify SRA determines the total number of pseudouridines. mPus3p and SRA are mainly cytoplasmic; however, mPus3p and SRA are also localized in distinct nuclear subcompartments. Finally, we identified an in vivo modified position in SRA, U206, which is likely a common target for both mPus1p and mPus3p. When U206 is mutated to A, SRA becomes hyperpseudouridylated in vitro, and it acquires dominant-negative activity in vivo. Thus, Pus1p- and Pus3p-dependent pseudouridylation of SRA is a highly complex posttranscriptional mechanism that controls a coactivator-corepressor switch in SRA with major consequences for NR signaling.
3T3 Cells↗
Modulation of Igf2 genomic imprinting in mice induced by 5-azacytidine, an inhibitor of DNA methylation.
The adjacent genes, insulin-like growth factor 2 (Igf2) and H19, are imprinted in both mouse and human. While Igf2 is expressed from the paternal allele, H19 is transcribed exclusively from the maternal allele. To explore the underlying mechanism of Igf2 and H19 imprinting, we studied the effect of DNA demethylation on allelic expression by injecting mice with the demethylating agent 5-azacytidine (5-aza-C). We observed a > or = 2-fold increase in the abundance of Igf2 mRNA in liver from treated mice compared with that of control mice. There was no significant change in Igf2 or H19 expression in brain. In the 5-aza-C-treated mice, there was dramatic modulation of Igf2 imprinting. In some tissues, Igf2 was expressed biallelically, while in other tissues, the paternal allele was silenced and the normally imprinted maternal allele was expressed, an example of allelic switching. There was no change in the normal biallelic pattern of Igf2 expression in brain. H19, on the other hand, remained imprinted in all tissues in mice treated with 5-aza-C. These results provide the first example of a pharmacological manipulation of genomic imprinting of an endogenous gene in vivo and further implicate DNA methylation as an important factor in maintaining the differential allelic expression of the Igf2 gene.
Animals↗
Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation.
Steroid receptor RNA activator (SRA) is a novel coactivator for steroid receptors that acts as an RNA molecule, whereas steroid receptor coactivator (SRC) family members, such as steroid receptor coactivator-1 (SRC-1) and transcriptional intermediary factor 2 (TIF2) exert their biological effects as proteins. Individual overexpression of each of these coactivators, which can form multimeric complexes in vivo, results in stimulated ERalpha transcriptional activity in transient transfection assays. However there is no information on the consequences of reducing SRC-1, TIF2, or SRA expression, singly or in combination, on ERalpha transcriptional activity. We therefore developed antisense oligodeoxynucleotides (asODNs) to SRA, SRC-1, and TIF2 mRNAs, which rapidly and specifically reduced the expression of each of these coactivators. ERalpha-dependent gene expression was reduced in a dose-dependent fashion by up to 80% in cells transfected with these oligonucleotides. Furthermore, treatment of cells with combinations of SRA, SRC-1, and TIF2 asODNs reduced ERalpha transcriptional activity to an extent greater than individual asODN treatment alone, suggesting that these coactivators cooperate, in at least an additive fashion, to activate ERalpha-dependent target gene expression. Finally, treatment of MCF-7 cells with asODN against SRC-1 and TIF2 revealed a requirement of these coactivators, but not SRA, for hormone-dependent DNA synthesis and induction of estrogen-dependent pS2 gene expression, indicating that SRA and SRC family coactivators can fulfill specific functional roles. Taken together, we have developed a rapid method to reduce endogenous coactivator expression that enables an assessment of the in vivo role of specific coactivators on ERalpha biological action and avoids potential artifacts arising from overexpression of coactivators in transient transfection assays.
Blotting, Western↗
Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats.
We investigated a family manifesting progressive ataxia, with expanded SCA8 CTA/CTG repeats. Neuropathologically, degeneration of Purkinje, inferior olivary, and nigral neurons and periaqueductal gliosis were evident. The sites of Purkinje cell loss were occupied by fibrillary accumulations. The remaining Purkinje cells showed somatic sprouts, and intracytoplasmic 1C2-positive granular structures were recognizable. This characteristic distribution of neurodegeneration and Purkinje cell cytopathology were distinct from those of other hereditary spinocerebellar ataxias previously reported.
Adult↗
SCA8 repeat expansions in ataxia: a controversial association.
The observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. The authors found allele sizes within the proposed pathogenic range in three patients with ataxia of unknown etiology, in two individuals from pedigrees with either SCA2 or Friedreich's ataxia, and in two patients with Alzheimer's disease. Sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold is determined.
Adult↗
De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation.
Xist (X-inactive specific transcript) plays a crucial role in X-inactivation. This non-coding RNA becomes upregulated on the X chromosome that is to be inactivated upon differentiation. Previous studies have revealed that although maintenance-type DNA methylation is not essential for X-inactivation to occur, it is required for the stable repression of Xist in differentiated cells. However, it is unknown whether differential de novo methylation at the Xist promoter, which is mediated by Dnmt3a and/or Dnmt3b, is a cause or a consequence of monoallelic expression of Xist. We show that Xist expression is appropriately regulated in the absence of Dnmt3a and Dnmt3b and that a single X chromosome undergoes proper inactivation in mutant females. Our results indicate that a mechanism(s) other than DNA methylation plays a principal role in initiating X-inactivation. We also demonstrate that delayed upregulation of Xist does not induce X-inactivation, consistent with a crucial developmental window for the chromosomal silencing.
Animals↗
Selective loss of imprinting in the placenta following preimplantation development in culture.
Preimplantation development is a period of dynamic epigenetic change that begins with remodeling of egg and sperm genomes, and ends with implantation. During this time, parental-specific imprinting marks are maintained to direct appropriate imprinted gene expression. We previously demonstrated that H19 imprinting could be lost during preimplantation development under certain culture conditions. To define the lability of genomic imprints during this dynamic period and to determine whether loss of imprinting continues at later stages of development, imprinted gene expression and methylation were examined after in vitro preimplantation culture. Following culture in Whitten's medium, the normally silent paternal H19 allele was aberrantly expressed and undermethylated. However, only a subset of individual cultured blastocysts (approximately 65%) exhibited biallelic expression, while others maintained imprinted H19 expression. Loss of H19 imprinting persisted in mid-gestation conceptuses. Placental tissues displayed activation of the normally silent allele for H19, Ascl2, Snrpn, Peg3 and Xist while in the embryo proper imprinted expression for the most part was preserved. Loss of imprinted expression was associated with a decrease in methylation at the H19 and Snrpn imprinting control regions. These results indicate that tissues of trophectoderm origin are unable to restore genomic imprints and suggest that mechanisms that safeguard imprinting might be more robust in the embryo than in the placenta.
Alleles↗
Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes.
The Insulin-like growth factor 2 (Igf2) and H19 genes are reciprocally imprinted and closely linked. Igf2 encodes a fetal growth-factor and is predominantly expressed from the paternal allele, while H19 is expressed from the maternal allele and encodes a transcript which may downregulate cellular proliferation. One of the epigenetic modifications thought to be involved in parental imprinting is DNA methylation. Here we analyse methylation in two regions of the Igf2 gene, one approx. 3 kb upstream of the gene and one in the 3' part of the gene. Both regions are more methylated on the expressed paternal chromosome. Genomic sequencing of individual chromosomes in the first region shows this parent-specific methylation to be highly mosaic; interestingly, individual sperm chromosomes carry different methylation patterns into the egg. In the more 3' region, which is fully methylated in sperm, the level of methylation on the paternal allele is highly tissue-specific and is correlated with expression of the gene in fetal tissues. Hence, the paternal allele is highly methylated in fetal liver (high expression) but is undermethylated in fetal brain (virtually no expression). Adult choroid plexus, a brain tissue in which Igf2 is expressed from both alleles and H19 is not expressed, represents an apparent loss of imprinting. Here, both Igf2 and H19 adopt a paternal type methylation pattern on both parental chromosomes. Analysis of early-passage androgenetic and parthenogenetic embryonic stem (ES) cells shows that the methylation patterns of Igf2 and H19 on maternal and paternal chromosomes are very similar. Androgenetic and parthenogenetic teratomas derived from these ES cells show the appropriate paternal and maternal patterns, respectively, of allelic methylation in both genes. Our results suggest that allelic methylation patterns in Igf2 and H19 arise early in embryogenesis and change progressively during development. Some of these developmental changes are apparently under tissue-specific control.
Alleles↗
Quantitative RT-PCR assays show Xist RNA levels are low in mouse female adult tissue, embryos and embryoid bodies.
We have investigated expression of the Xist gene in mouse female adult kidney, embryos and embryonic stem (ES) cells undergoing in vitro differentiation as embryoid bodies. Using the quantitative RT-PCR single nucleotide primer extension (SNuPE) assay, we found that the amount of Xist RNA in adult kidney of three mouse strains was less than approximately 2000 transcripts per cell, with only modest differences between strains carrying different Xce alleles. Female embryos 7.5 days post coitum had the same number of Xist transcripts per cell as isogenic adult tissue. Using quantitative oligonucleotide hybridization assays after RT-PCR, we investigated Xist expression in ES lines heterozygous at the Pgk-1 and Xist loci. We found that, while in most (XX) ES lines Xist RNA levels increased during embryoid body formation, the levels seen were less than 10% those found in adult female kidney. In addition, we found that the allelic ratio of Xist transcripts from reciprocal (XX) ES cell lines differentiating in vitro was identical to that of isogenic 10.5 to 11.5 day female embryos. These latter results suggest that there is no pattern of preferential paternal imprinting during days 1 to 9 of in vitro differentiation of ES cells. However, the influence of the Xce locus on the randomness of X-inactivation in embryos seems to operate also in ES cell lines. Our overall conclusion is that the low levels of Xist RNA in female kidney, embryos and differentiating (XX) ES cells are compatible only with models that do not require Xist RNA to cover the entire inactive X chromosome.
Animals↗
Temporal and spatial regulation of H19 imprinting in normal and uniparental mouse embryos.
The mouse H19 gene is imprinted so that the paternal copy is both methylated and repressed during fetal development. However, the CpG-rich promoter region encompassing the transcription start is not methylated in sperm; this region must therefore become methylated postzygotically. We first examined the timing of DNA methylation of this region and the corresponding expression of H19. Both parental copies are initially undermethylated in blastocysts and the paternal copy then becomes fully methylated in the embryo around implantation; this methylation is more protracted in the extraembryonic lineages, especially in the trophoblast. By contrast to the lineage-dependent methylation, we observed exclusive expression of the maternal copy in preimplantation embryos and in all the lineages of early postimplantation embryos although variability may exist in cultured embryos. This indicates that methylation of the CpG-rich promoter is not a prerequisite for the paternal repression. We then examined whether methylation and expression occurs appropriately in the absence of a maternal or a paternal genome. Both H19 copies in androgenetic embryos are fully methylated while they are unmethylated in parthenogenetic embryos. This correlates with the lack of expression in androgenetic embryos but expression in parthenogenetic embryos. However, the androgenetic trophoblast was exceptional as it shows reduced methylation and expresses H19. These results suggest that promoter methylation is not the primary inactivation mechanism but is a stabilizing factor. Differential methylation in the more upstream region, which is established in the gametes, is a likely candidate for the gametic signal and may directly control H19 activity.
Animals↗