Genomic imprinting: implications for human disease.
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ABSTRACT:
SUBMITTER: Falls JG
PROVIDER: S-EPMC1866410 | biostudies-literature | 1999 Mar
REPOSITORIES: biostudies-literature
Publications
Genomic imprinting: implications for human disease.
Falls J G JG Pulford D J DJ Wylie A A AA Jirtle R L RL
The American journal of pathology 19990301 3
Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. This parent-of-origin dependent phenomenon is a notable exception to the laws of Mendelian genetics. Imprinted genes are intricately involved in fetal and behavioral development. Consequently, abnormal expression of these genes results in numerous human genetic disorders including carcinogenesis. This paper reviews genomic imprinting and its role in human disease. Additional information about impr ...[more]
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Project description:BackgroundGenomic imprinting (GI) is a mammalian-specific epigenetic phenomenon that has been implicated in the evolution of the placenta in mammals.MethodsEmbryo transfer procedures and trophoblast stem (TS) cells were used to re-examine mouse placenta-specific GI genes. For the analysis of human GI genes, cytotrophoblast cells isolated from human placental tissues were used. Using human TS cells, the biological roles of human GI genes were examined.Main findings(1) Many previously identified mouse GI genes were likely to be falsely identified due to contaminating maternal cells. (2) Human placenta-specific GI genes were comprehensively determined, highlighting incomplete erasure of germline DNA methylation in the human placenta. (3) Human TS cells retained normal GI patterns. (4) Complete hydatidiform mole-derived TS cells were characterized by aberrant GI and enhanced trophoblastic proliferation. The maternally expressed imprinted gene p57KIP2 may be responsible for the enhanced proliferation. (5) The primate-specific microRNA cluster on chromosome 19, which is a placenta-specific GI gene, is essential for self-renewal and differentiation of human TS cells.ConclusionGenomic imprinting plays diverse and important roles in human placentation. Experimental analyses using TS cells suggest that the GI maintenance is necessary for normal placental development in humans.
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Project description:More than a hundred protein-coding genes are controlled by genomic imprinting in humans. These atypical genes are organized in chromosomal domains, each of which is controlled by a differentially methylated "imprinting control region" (ICR). How ICRs mediate the parental allele-specific expression of close-by genes is now becoming understood. At several imprinted domains, this epigenetic mechanism involves the action of long non-coding RNAs. It is less well appreciated that imprinted gene domains also transcribe hundreds of microRNA and small nucleolar RNA genes and that these represent the densest clusters of small RNA genes in mammalian genomes. The evolutionary reasons for this remarkable enrichment of small regulatory RNAs at imprinted domains remain unclear. However, recent studies show that imprinted small RNAs modulate specific functions in development and metabolism and also are frequently perturbed in cancer. Here, we review our current understanding of imprinted small RNAs in the human genome and discuss how perturbation of their expression contributes to disease.
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Project description:A subset of genes in mammals are subject to genomic imprinting. The mouse H19 gene, for example, is active only when maternally inherited and the neighboring Igf2 gene is paternally expressed. This imprinted expression pattern is regulated by the imprinting control region (ICR) upstream of the H19 gene. A maternally inherited H19 ICR inhibits Igf2 gene activation by the downstream enhancer due to its insulator function while it suppresses H19 gene transcription by promoter DNA methylation when paternally inherited. These parent-of-origin specific functions depend on the allele-specific methylation of the ICR DNA, which is established during gametogenesis. Therefore, the ICR may also function as a landmark for epigenetic modifications. To examine whether the ICR confers these activities autonomously, we introduced a 2.9-kbp ICR-containing DNA fragment into a human beta-globin yeast artificial chromosome at the 3' end of the locus control region and established transgenic mouse lines. Expression of all of the beta-like globin genes was higher when the transgene was paternally inherited. In accord with this result, transgenic ICR DNA from nucleated erythrocytes was more heavily methylated when paternally transmitted. Chromatin immunoprecipitation assays confirmed that CCCTC binding factor is preferentially recruited to the maternal transgenic ICR in vivo. Surprisingly however, the parent-of-origin specific methylation pattern was not observed in germ cell DNA in testis, demonstrating that methylation was established after fertilization. Thus, the ICR autonomously recapitulated imprinting within the normally nonimprinted transgenic beta-globin gene locus, but the temporal establishment of imprinting methylation differs from that at the endogenous Igf2/H19 locus.
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Project description:To detect potentially imprinted, obesity-related genetic loci, we performed genomewide parent-of-origin linkage analyses under an allele-sharing model for discrete traits and under a family regression model for obesity-related quantitative traits, using a European American sample of 1,297 individuals from 260 families, with 391 microsatellite markers. We also used two smaller, independent samples for replication (a sample of 370 German individuals from 89 families and a sample of 277 African American individuals from 52 families). For discrete-trait analysis, we found evidence for a maternal effect in chromosome region 10p12 across the three samples, with LOD scores of 5.69 (single-point) and 4.52 (multipoint) for the pooled sample. For quantitative-trait analysis, we found the strongest evidence for a maternal effect (single-point LOD of 2.85; multipoint LOD of 4.01 for body mass index [BMI] and 3.69 for waist circumference) in region 12q24 and for a paternal effect (single-point LOD of 4.79; multipoint LOD of 3.72 for BMI) in region 13q32, in the European American sample. The results suggest that parent-of-origin effects, perhaps including genomic imprinting, may play a role in human obesity.
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Project description:BACKGROUND: hiPSCs are generated through epigenetic reprogramming of somatic tissue. Genomic imprinting is an epigenetic phenomenon through which monoallelic gene expression is regulated in a parent-of-origin-specific manner. Reprogramming relies on the successful erasure of marks of differentiation while maintaining those required for genomic imprinting. Loss of imprinting (LOI), which occurs in many types of malignant tumors, would hinder the clinical application of hiPSCs. RESULTS: We examined the imprinting status, expression levels and DNA methylation status of eight imprinted genes in five independently generated hiPSCs. We found a low frequency of LOI in some lines. Where LOI was identified in an early passage cell line, we found that this was maintained through subsequent passages of the cells. Just as normal imprints are maintained in long-term culture, this work suggests that abnormal imprints are also stable in culture. CONCLUSIONS: Analysis of genomic imprints in hiPSCs is a necessary safety step in regenerative medicine, with relevance both to the differentiation potential of these stem cells and also their potential tumorigenic properties.
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Project description:Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues.
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Project description:Somatic-cell hybrids have been shown to maintain the correct epigenetic chromatin states to study developmental globin gene expression as well as gene expression on the active and inactive X chromosomes. This suggests the potential use of somatic-cell hybrids containing either a maternal or a paternal human chromosome as a model system to study known imprinted genes and to identify as-yet-unknown imprinted genes. Testing gene expression by using reverse transcription followed by PCR, we show that functional imprints are maintained at four previously characterized 15q11-q13 loci in hybrids containing a single human chromosome 15 and at two chromosome 11p15 loci in hybrids containing a single chromosome 11. In contrast, three gamma-aminobutyric acid type A receptor subunit genes in 15q12-q13 are nonimprinted. Furthermore, we have found that differential DNA methylation imprints at the SNRPN promoter and at a CpG island in 11p15 are also maintained in somatic-cell hybrids. Somatic-cell hybrids therefore are a valid and powerful system for studying known imprinted genes as well as for rapidly identifying new imprinted genes.
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Project description:Imprinted genes represent a curious defiance of normal Mendelian genetics. Mammals inherit two complete sets of chromosomes, one from the mother and one from the father, and most autosomal genes will be expressed from both the maternal and the paternal alleles. Imprinted genes, however, are expressed from only one chromosome, in a parent-of-origin-dependent manner. Because silent and active promoters are present in a single nucleus, the differences in activity cannot be explained by transcription-factor abundance. Thus, transcription of imprinted genes represents a clear situation in which epigenetic mechanisms restrict gene expression and, therefore, offers a model for understanding the role of DNA modifications and chromatin structure in maintaining appropriate patterns of expression. Furthermore, because of their parent-of-origin-restricted expression, phenotypes determined by imprinted genes are susceptible not only to genetic alterations in the genes but also to disruptions in the epigenetic programs controlling regulation. Imprinted genes are often associated with human diseases, including disorders affecting cell growth, development, and behavior.
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