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5 - Epigenetic regulation of gene expression, Bird & Jaenisch.doc

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David Rollo

Article #5 • Cells of a multicellular organism are genetically homogeneous, but structurally and functionally heterogeneous b/c of different gene expression • Epigenetics or “outside conventional genetics” - describes the study of stable alterations in gene expression potential that arise during development & cell proliferation • Such epigenetic processes are essential for development & differentiation, but they can also arise in mature humans & mice, either by random change or under environ influence • also guard against viral genomes that would otherwise hijack cellular fn • modification of DNA or proteins are recognized by specific proteins that recognize modifications and facilitate the appropriate biological effects Establishing and maintaining patterns of DNA methylation • DNA methylation o chief contributor to stability of gene expression states, might be responsible for stable maintenance of particular gene expression pattern through mitotic cell division and is involved in maintaining X chromosome inactivation in females o DNA methylation est. a silent chromatin state by collaborating with protein that modify nucleosomes o Post replication modification o DNA methylation found in cytosines of the dinucleotide sequence CpG • Extent of DNA methylation changes during mammalian development: o Wave of demethylation during cleavage o Genome wide methylation after implantation o Demethylation is an active process that strips the male genome of methylation within hours of fertilization. o Maternal genome is only passively demethylated during cleavage divisions o methylation decreases in specific tissues during differentiation o methylation occurs rarely in postgastrulation – but is seen in cancer! • DNA methyltransferases (DNMT):  DNMT1 maintenance methylrtansferase (i.e. maintains but not est maternal imprint), absence results in global demethylation and embryonic lethality, DNMT1o  responsible for maintaining, but not establishing maternal imprints  DNMT3a, DNMT3b  methylation after implantation, expressed highly during developing embryo  DNMT3L  no DNMT activity on own but joins to DNMT3a/b to imprint on female germ line  DNMT2  no DNMT alone, may be responsible for small amount of non-Cpg methylation in flied • DNA meth is essential for vertebrate development • Loss of methylation causes apoptosis in embryos/fibroblasts, NOT in stem cells, or cancer cells, depression of extopic gene expression, and transcriptional activation of transposable elements • Evolution explanation of methylation  mechanism to silence transposable elements? Mediate transcriptional noise reduction? Yet to be resolved • Non embryonic cells  80% CpG’s are methylated • CpG islands are associated with genes and all may contain promoters • methylation is interrupted by short CpG islands  generally unmethylated all the time (few exceptions), if methylated leads to long term shut down of the gene • cancer cells  methylation of CpG islands can contribute to gene silencing • histone modifications may also tirigger methylation of DNA • DNA methylation acts as a system of cellular memory that isn’t directly involved in intiating gene silencing, but senses and propogates the silent state • Methyl-CpG-binding domain proteins (MBDs) like MeCP2 recruit chromatin remodelling things… • Histone deacetylation (HDAC’s) SO….methylation doesn`t directly shut off genes, it does so my recruiting other genes that affect histone modification such as deacetylases!!!! • DNA methylation is just one component of a wider epigenetic program that includes other postsynthesis modifications of chromatin  make feedback loops so ensure the polarization of chromatin domains so that self-reinforcing steps are present to prevent going in other direction (pulls back to “pole”) Interpreting the DNA methylation signal • Several ways that methylation can repress transcription: 1. exclusion of proteins that affect transcription by the methylation blocking their binding sites o CpG methylation blocks the binding of chromatin boundary element binding protein (CTCF – blocks interactions between promoter and enhancer) 2. Methyl-CpG-binding domain proteins (MBDs): o DNA methlylation is repulsive to some DNA binding proteins but attractive to others o mediators of transcriptional repression o Includes MeCP2 and MBD 1-4 o Transciptionally repress MeCP2 interacts with a corepressor complexes containing HDAC’s (histone deacetylases)  shows that there is an interaction between DNA methylation and histone modification o mice without MBD2 are viable and fertile but lack methylating DNA binding complex MeCP1  defective in the methylation- mediated of genes and significant gene depression - MBD proteins then recruit additional proteins to the locus, such as histon
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