DNA Methylation and HydroxymethylationImprinting and Inheritance

Genomic imprinting – new insight into the methylation patterns of humans

Gene imprintingGenomic imprinting is an epigenetic gene-marking phenomenon that is mostly established in germline and results in monoallelic gene expression according to parental origin.1 The process of genomic imprinting is associated with prenatal development providing functions necessary for normal fetal growth. In addition to prenatal expression, postnatal gene imprinting may also occur, mainly in the brain, likely influencing personal and parenting behavioural, cognitive and emotional characteristics.2 Recently the focus of the research of imprinted genes has shifted from placenta to postnatal somatic tissues, aiming to provide more detailed biological data and evolutionary explanations to parent-specific gene dosage in pre- and postnatal origin of diseases.

It is important to note that studying of imprinted genes cannot avoid characterization of imprinting control regions (ICRs) that solely can regulate expression of an entire cluster of imprinted genes. Gene imprinting is primarily achieved by silencing of one parental allele via methylation of CpG-rich islands located at ICRs.3,4 Therefore, more intermediately methylated CpG sites are expected in imprinted genes and their ICRs. However, the question of whether imprinted genes also retain the same methylation pattern in somatic tissues of adult humans has, so far, remained unclear. We therefore aimed to perform the analysis of methylation status of the imprinted genes and their regulative ICRs in 18 somatic tissue of adult individuals.

Our study has demonstrated that imprinted genes indeed have their own specific methylation pattern characterized by increased number on intermediately methylated probes along the entire length of a gene with the highest concentration in the specific promoter area, allocated on 200-1500 base pairs from transcription start site. The relationship between high and low promoter methylation with gene expression is not a new idea itself. Nevertheless, to our knowledge, the current study is the first to provide compelling evidence that imprinted genes maintain an intermediately methylated status in somatic tissues of adult humans, even when the ICR-related CpG sites were excluded.

Levene’s test used in our study revealed another important detail in studying imprinted genes. In our study we used a wide range of tissues, formed from all three germ layers during embryogenesis. Tissue sample panel was complimented with blood samples from healthy donors. The results of Levene’s test provided assurance that blood samples are a valuable source of DNA for imprinting studies.

The current study strongly supports the recently raised hypothesis in the seminal paper of Court et al. that substantiates the distribution of germline ICRs between ubiquitously imprinted and placenta-specific imprinted genes.3 Our study demonstrated remarkable stability of intermediate methylation status across all somatic tissues tested. In contrast, the placenta-specific ICRs keep low methylation status. It is well known that high levels of expression are often associated with low levels of methylation in somatic tissues, leading us to the idea that genes found to be imprinted in placenta tissue could avoid monoallelic expression in adult somatic tissues. An interesting find was represented in another recent paper of Hanna et al. They demonstrated the intermediate methylation status of the same placenta-specific ICRs in both inner cell mass and trophectoderm samples. The authors suggested that these regions are transiently imprinted in embryo, not just extra-embryonic.5 All these discoveries together lead us to a new hypothesis of a new mechanism of independent establishment of imprinted genes in adult human body. Personally, as a researcher, I feel that the process of genomic imprinting is still a terra incognita and future studies are required to provide a deeper understanding of the regulation and establishment of imprinted genes in somatic tissues throughout the whole human lifespan.

Original Article:

Pervjakova N, Kasela S, Morris AP, Kals M, Metspalu A, Lindgren CM, Salumets A, & Mägi R (2016). Imprinted genes and imprinting control regions show predominant intermediate methylation in adult somatic tissues. Epigenomics PMID: 27004446

References:

1. McGrath J, & Solter D (1984). Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell, 37 (1), 179-83 PMID: 6722870

2. Renfree MB, Suzuki S, & Kaneko-Ishino T (2013). The origin and evolution of genomic imprinting and viviparity in mammals. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 368 (1609) PMID: 23166401

3. Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simón C, Moore H, Harness JV, Keirstead H, Sanchez-Mut JV, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, & Monk D (2014). Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome research, 24 (4), 554-69 PMID: 24402520

4. Lopes, S. (2003). Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions Human Molecular Genetics, 12 (3), 295-305 DOI: 10.1093/hmg/ddg022

5. Hanna CW, Peñaherrera MS, Saadeh H, Andrews S, McFadden DE, Kelsey G, & Robinson WP (2016). Pervasive polymorphic imprinted methylation in the human placenta. Genome research, 26 (6), 756-67 PMID: 26769960

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Natalia Pervjakova

Natalia Pervjakova