Profiling of DNA methylation patterns as biomarkers of human disease
Kuupäev
2019-04-29
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
DNA-s sisalduv geneetiline informatsioon annab vajalikud juhised organismi kasvuks ja arenguks. Lisaks DNA nukleotiidsele järjestusele mõjutavad neid protsesse ka DNA-s esinevad modifikatsioonid. Enim uuritud DNA modifikatsioon on DNA metülatsioon, mis tähendab metüülrühma lisamist tsütosiini külge. DNA on tihtilugu metüleeritud regiooniti, moodustades niinimetatud metülatsioonimustreid. Need “mustrid“ osalevad geeniekspressiooni regulatsioonis, lülitades teatud rakkudes geene sisse ja välja või kohandades nende aktiivsust. On oluline märkida, et DNA metülatsioon on tugevalt mõjutatud keskkonnateguritest, nimelt vastavalt keskkonnatingimustele võidakse teatud regioone metüleerida või vastupidi, metüülrühmi eemaldada. Seega on DNA metülatsioon üheks vahelüliks geneetika ja keskkonna vahel. Paljud neist “mustritest“ on omased tavalistele bioloogilistele protsessidele, kuid leidub ka selliseid, mis viitavad haiguse olemasolule. Näiteks on spetsiifilisi metülatsioonimustreid täheldatud diabeedi, neuroloogiliste häirete ja vähi puhul. Seetõttu peetakse neid “mustreid“ ka headeks biomarkeri kandidaatideks, sobides iseloomustama näiteks teatud haiguste kulgu. Käesolev väitekiri keskendubki DNA metülatsiooni uurimisele erinevates kudedes ja seisundites, et leida potentsiaalseid biomarkereid. Selleks kasutati erinevaid bioinformaatika ja statistika meetodeid. Kokku viidi läbi kolm publitseeritud uuringut, mille käigus uuriti nii koe- kui endometrioosispetsiifilisi biomarkeri kandidaate kui ka DNA metülatsiooni muutusi emaka endomeetriumi embrüole vastuvõtlikuks muutumise perioodil. Lisaks arendati doktoritöö raames välja uudne ja kasutajasõbralik veebirakendus – MethSurv, mis kasutades suurprojekti “The Cancer Genome Atlas” (TCGA) andmeid, võimaldab kasutajal uurida vähipatsientide elumust konkreetse DNA metülatsioonil põhineva prognostiliste markeri põhjal.
DNA contains the genetic information required for the growth and development of the organism. In addition to the nucleotide sequence, certain chemical modifications influence the activity of the DNA. The most studied DNA modification is DNA methylation, where a methyl group is added to the cytosine base of the DNA. DNA is often methylated within a genomic region, forming so-called “methylation patterns.” These "patterns" are involved in the regulation of gene expression by switching genes in and out of certain cells or adjusting their activity. Environmental factors strongly influence DNA methylation; wherein certain genomic regions may be methylated or unmethylated. Thus, methylation patterns serve as a mediator between the environment and genomes. Many of these "patterns" are inherited in normal biological processes. However, some of these patterns indicate the presence of the disease. For example, specific methylation patterns have been observed in diabetes, neurological disorders, and cancer. Therefore, methylation patterns are considered as biomarker candidates to characterize the progression of certain diseases or normal biological process. This thesis focuses on the study of DNA methylation in different tissues and conditions to identify potential biomarker candidates using various bioinformatics and statistical methods. In total, three studies were included in this thesis to investigate both tissue and endometriosis-specific biomarker candidates as well as changes in DNA methylation during the transition from pre-receptive to the receptive state of the endometrium. In addition, a novel and user-friendly web application MethSurv was developed in this thesis. MethSurv uses methylation and clinical data from the publicly available “The Cancer Genome Atlas” (TCGA). The MethSurv tool is aimed at assisting the scientific community in exploring methylation-based prognostic biomarkers.
DNA contains the genetic information required for the growth and development of the organism. In addition to the nucleotide sequence, certain chemical modifications influence the activity of the DNA. The most studied DNA modification is DNA methylation, where a methyl group is added to the cytosine base of the DNA. DNA is often methylated within a genomic region, forming so-called “methylation patterns.” These "patterns" are involved in the regulation of gene expression by switching genes in and out of certain cells or adjusting their activity. Environmental factors strongly influence DNA methylation; wherein certain genomic regions may be methylated or unmethylated. Thus, methylation patterns serve as a mediator between the environment and genomes. Many of these "patterns" are inherited in normal biological processes. However, some of these patterns indicate the presence of the disease. For example, specific methylation patterns have been observed in diabetes, neurological disorders, and cancer. Therefore, methylation patterns are considered as biomarker candidates to characterize the progression of certain diseases or normal biological process. This thesis focuses on the study of DNA methylation in different tissues and conditions to identify potential biomarker candidates using various bioinformatics and statistical methods. In total, three studies were included in this thesis to investigate both tissue and endometriosis-specific biomarker candidates as well as changes in DNA methylation during the transition from pre-receptive to the receptive state of the endometrium. In addition, a novel and user-friendly web application MethSurv was developed in this thesis. MethSurv uses methylation and clinical data from the publicly available “The Cancer Genome Atlas” (TCGA). The MethSurv tool is aimed at assisting the scientific community in exploring methylation-based prognostic biomarkers.
Kirjeldus
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Märksõnad
DNA metüülimine, koed, vähk (med.), elulemus, biomarkerid, bioinformaatika