Genomic imprinting in complex traits
Abstract
Juba 1980. aastate alguses läbi viidud katsed loomade rakutuumade siirdamisega tõid esile epigeneetilise nähtuse, mida hakati nimetama geneetiliseks vermimiseks (genomic imprinting). Selle fenomeni tõttu tekivad vanemaspetsiifilised erinevused geenide ekspressioonis. Diploidses organismis ekspresseeruvad tavaliselt mõlemalt vanemalt päritud geenikoopiad. Vermitud geenide puhul ekspresseerub ainult üks geenikoopia, samas kui teine koopia on inaktiveeritud. Nüüdseks on inimestel leitud juba peaaegu 150 vermitud geeni. Kuna geneetilise vermimise eeldused tekivad sugurakkudes, arvati pikka aega, et see muster püsib sarnasena kõikides kudedes. Uuemad tööd, milles on kasutatud inimeste ja katseloomade erinevaid rakke on siiski näidanud, et vermitud geenide ekspressioonimuster sõltub nii koest kui ka organismi arengujärgust. Enamik vermitud geene on leitud platsentast või embrüonaalsetest kudedest ning on vähe informatsiooni samade geenide ekspressioonimustrite kohta täiskasvanud organismi kudedes. Seetõttu on oluline uurida iga vermitud geeni vermimismudelit erinevates kudedes, et oleks võimalik hinnata selle geeni mõju haigusele.
Käesoleva töö raames uurisime vermitud geenide ning nendega seotud kontrollregioonide metülatsioonimustreid, kasutades selleks täiskasvanud inimese somaatilisi kudesid. Koeproovide uurimisel leidsime, et vermitud geene iseloomustab promootori-spetsiifilises piirkonnas suurema arvu poolmetüleeritud nukleotiidide esinemine, mis võib viidata vanema-spetsiifilisele metülatsioonile. Lisaks tuvastasime, et ICR-id geeniregioonides, mis olid algselt vermitud sugurakkudes ehk ootsüütides ja spermatosoidides, võivad hiljem somaatilistes rakkudes oma poolmetüleeritud oleku kaotada. Hilisemad uuringud on seostanud poolmetüleeritud oleku kadu geenide bialleelse ekspressiooniga. Seetõttu on alust oletada, et, platsentas vermitud geenid võivad hilisemates arengustaadiumites omada bialleelset ekspressiooni.
In the early 1980 the animal nucleus transplantation experiments revealed an epigenetic phenomenon, later called as genomic imprinting, resulting in genes expressed in a parent-of-origin manner. In diploid organism, the somatic cells express both parental copies of a gene, whereas imprinted genes demonstrate expression only from one allele, while the second one remains deactivated. As for 2018, nearly 150 imprinted genes have been identified in humans. Being established in the germline, genomic imprints were thought to have identical patterns within an organism. Later, studies in animals and humans have demonstrated that the expression of imprinted genes may depend on the specific tissue and the developmental stage of an organism. To date most of the genes has been detected as imprinted in placenta or embryonic tissues, and there is a limited information about imprinted expression in an adult organism. Thus comprehensive imprinted expression analysis would shed light onto the specific tissues and developmental stage of an organism. In this thesis we aimed to define the methylation patterns for imprinted genes and germline differentially methylated regions in somatic tissues of adult organisms. We identified an imprinting-specific methylation pattern that is characterized by an increased number of intermediately methylated probes within a specific area of the promoter. We also detected the loss of methylation for placenta-specific germline DMRs. Thus, it is highly probable that genes that were detected as imprinted in placenta have biallelic expression in tissues somatic tissues of an organism.
In the early 1980 the animal nucleus transplantation experiments revealed an epigenetic phenomenon, later called as genomic imprinting, resulting in genes expressed in a parent-of-origin manner. In diploid organism, the somatic cells express both parental copies of a gene, whereas imprinted genes demonstrate expression only from one allele, while the second one remains deactivated. As for 2018, nearly 150 imprinted genes have been identified in humans. Being established in the germline, genomic imprints were thought to have identical patterns within an organism. Later, studies in animals and humans have demonstrated that the expression of imprinted genes may depend on the specific tissue and the developmental stage of an organism. To date most of the genes has been detected as imprinted in placenta or embryonic tissues, and there is a limited information about imprinted expression in an adult organism. Thus comprehensive imprinted expression analysis would shed light onto the specific tissues and developmental stage of an organism. In this thesis we aimed to define the methylation patterns for imprinted genes and germline differentially methylated regions in somatic tissues of adult organisms. We identified an imprinting-specific methylation pattern that is characterized by an increased number of intermediately methylated probes within a specific area of the promoter. We also detected the loss of methylation for placenta-specific germline DMRs. Thus, it is highly probable that genes that were detected as imprinted in placenta have biallelic expression in tissues somatic tissues of an organism.
Description
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Keywords
somatic cells, nucleotides, methylation, phenotype, metabolites