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

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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

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

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