Novel genetic and epigenetic alterations in ... - Ous-research.no
Novel genetic and epigenetic alterations in ... - Ous-research.no Novel genetic and epigenetic alterations in ... - Ous-research.no
Introductionmethylation during embryogenesis, and by such establish novel methylation marks on theDNA[8;26]. Some genes, including imprinted genes, are inherited via the germ line[27;28].How epigenetic information can be passed via germ cells is still unclear as a substantialepigenetic re-programming takes place during early embryogenesis, often thought of as anerasure of methylation marks.Promoter hypermethylation impair gene expression by preventing transcription factors tobind to DNA. This occurs in two ways, either by direct inhibition of the binding oftranscription factors to the methylated sequence[29;30], or via recruitment of proteins with amethyl binding domain (MBD protein family) which leads to condensation of the chromatinstructure by the means of histone deacetylation (reviewed in [31])(Figure 3). Knocking outMBD-proteins with RNA interference re-introduces transcription of initially inactive geneswithout altering the methylation status, thereby clearly demonstrating the role of MBDs as alink between promoter hypermethylation and gene expression[32]. Still, the role of mutationsin either of the MBD genes are unclear[33;34].16
IntroductionFigure 3. Methylation effect on chromatin. In an expressed state, the chromatin structure in proximity tothe gene is loosely packed, a state recognized by acetylation of the histone tails (i). The adding of methyl groupsto the CpG sites (ii) is associated with a more densely packed chromatin and can be obtained in several ways. Afamily of proteins with a methyl-binding domain (MBD) binds to the DNA-bound methyl groups. Dependingon which protein that binds, the binding partners and the effects vary slightly (iii – v). The net effect is thatRNA transcription is impaired due to blocking of transcription factors, either by inhibiting the direct binding(vi) or by condensation of the chromatin structure (vii).17
- Page 1 and 2: Novel genetic and epigenetic altera
- Page 3 and 4: TABLE OF CONTENTSACKNOWLEDGEMENTS .
- Page 5 and 6: ACKNOWLEDGEMENTSThe present work ha
- Page 7 and 8: Prefacetechnology[3]. This new tech
- Page 10 and 11: SummaryThe subgroup of carcinomas w
- Page 12 and 13: Introduction“Epigenetic inheritan
- Page 14 and 15: Introductionamino acid change it is
- Page 18 and 19: IntroductionDNA is most of the time
- Page 20 and 21: IntroductionFigure 5. DNA methylati
- Page 22 and 23: IntroductionFigure 6. Incidence rat
- Page 24 and 25: IntroductionFigure 8. Tumor staging
- Page 26 and 27: Introductioninasmuch as 80% of colo
- Page 28 and 29: IntroductionInstabilities involved
- Page 30 and 31: Introductionthere seems to be a fid
- Page 32 and 33: Introductionsevere alterations are
- Page 34 and 35: Introductionpopulation-wide screeni
- Page 36 and 37: IntroductionFigure 12. Present and
- Page 38 and 39: RESULTS IN BRIEFPaper Ia. “DNA hy
- Page 40 and 41: Results in Briefinstability, and se
- Page 42 and 43: Results in BriefUnivariate survival
- Page 44 and 45: Discussionseveral factors, and full
- Page 46 and 47: Discussionlow threshold, we increas
- Page 48 and 49: DiscussionIt may seem like unnecess
- Page 50 and 51: Discussionthan 96% DHPLC do not sta
- Page 52 and 53: DiscussionFigure 13. Mutation detec
- Page 54 and 55: DiscussionClinical impact of molecu
- Page 56 and 57: Discussionmarkers with a very high
- Page 58 and 59: Discussionchromosomes in metaphase[
- Page 60 and 61: DiscussionThese examples underline
- Page 62 and 63: Discussiongenes. One is based on mu
- Page 64 and 65: CONCLUSIONSWe have identified novel
Introductionmethylation dur<strong>in</strong>g embryogenesis, <strong>and</strong> by such establish <strong>no</strong>vel methylation marks on theDNA[8;26]. Some genes, <strong>in</strong>clud<strong>in</strong>g impr<strong>in</strong>ted genes, are <strong>in</strong>herited via the germ l<strong>in</strong>e[27;28].How epi<strong>genetic</strong> <strong>in</strong>formation can be passed via germ cells is still unclear as a substantialepi<strong>genetic</strong> re-programm<strong>in</strong>g takes place dur<strong>in</strong>g early embryogenesis, often thought of as anerasure of methylation marks.Promoter hypermethylation impair gene expression by prevent<strong>in</strong>g transcription factors tob<strong>in</strong>d to DNA. This occurs <strong>in</strong> two ways, either by direct <strong>in</strong>hibition of the b<strong>in</strong>d<strong>in</strong>g oftranscription factors to the methylated sequence[29;30], or via recruitment of prote<strong>in</strong>s with amethyl b<strong>in</strong>d<strong>in</strong>g doma<strong>in</strong> (MBD prote<strong>in</strong> family) which leads to condensation of the chromat<strong>in</strong>structure by the means of histone deacetylation (reviewed <strong>in</strong> [31])(Figure 3). K<strong>no</strong>ck<strong>in</strong>g outMBD-prote<strong>in</strong>s with RNA <strong>in</strong>terference re-<strong>in</strong>troduces transcription of <strong>in</strong>itially <strong>in</strong>active geneswithout alter<strong>in</strong>g the methylation status, thereby clearly demonstrat<strong>in</strong>g the role of MBDs as al<strong>in</strong>k between promoter hypermethylation <strong>and</strong> gene expression[32]. Still, the role of mutations<strong>in</strong> either of the MBD genes are unclear[33;34].16