Epigenetic Mechanisms in
Development and Disease

 

 

Transcriptional Repression by DNA Methylation?

It is widely accepted that symmetrically methylated CpGs (MeCpGs) act as a molecular tag that can recruit other proteins to DNA, namely the methyl-CpG binding domain repressor proteins (MBDs: MBD1, MBD2, MBD3, MeCP2, Kaiso, xKL1 and xKL2) 14.

 

Reference List

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1. Epigenetics

2. Expression of xDnmt1 mRNA during Xenopus Development (this page)
   

3. Transcriptional Repression by DNA Methylation?

4. Our Work

 

 

Expression of xDnmt1 mRNA during Xenopus Development

Whole mount RNA in situ analysis

 

Transcriptional Repression by DNA Methylation? (continued)

Other proteins in the sequence databases contain MBD type domains, such as MBD4, which is involved in DNA repair and not transcription repression 14. MBDs can in turn act as links between methylated DNA and multi-protein complexes (MeCP1, MeCP2/SMRT, Kaiso/Ncor) with HDAC and HMT activity that can potentially lead to the formation of a closed and condensed chromatin structure 15;17. Loss of methylation, by inactivation of Dnmts, can abrogate the cascade of events mentioned above, and this situation coupled with acetylated histones leads to a more open euchromatic structure that is amenable to active gene transcription 4.

xMeCP2 Expression During Xenopus Embryo Development

 

 

Inhibition of the maintenance methyltransferase activity, Dnmt1, in amphibians and mice leads to up regulation of many genes (up to 10% of expressed sequence tags (ESTs) in mice) 18;19. DNA methylation is utilised in many silencing processes including X chromosome inactivation, silencing of retroviruses and genomic imprinting whereby the mono-allelic expression pattern of an autosomal gene is determined by the parental origin of the gene 20;21. Recent work suggests that there are many emerging exceptions to the observation that CpG islands are not methylated during mammalian development. Profiling of CpG islands in a range of rodent somatic and germ cell tissues suggests that the methylation status of up to 18% of non-X-linked CpG islands is developmentally regulated 22;24.

 

Abnormal methylation patterns at gene promoters are associated with the progression of many cancers leading to the epigenetic silencing of essential cell cycle checkpoint genes that would normally participate in surveillance for cellular abnormalities 25;26. Inhibition of DNA methylation mediated silencing in cancer may prove to a useful therapy 27.

 

Mis-expression of xBF2 in stage 8 Xenopus laevis embryos with reduced amounts of xDnmt1 (xDMO)

 

xBf2 in situ Animal View