表观遗传-医学分子生物学.pptVIP

* * * In early embryogenesis, DNA is largely devoid of methylation (top left). Post implantation, de novo methylation begins (red circles), mediated primarily by DNA (cytosine-5-)-methyltransferase-3 (DNMT3A) and -3 (DNMT3B) (top). When methylation affects CpG islands, methyl-binding proteins trigger a silencing cascade (activity illustrated by green stars) whereby histone H3K9 is sequentially deaceylated and then methylated, allowing heterochromatin protein 1 (HP1) to bind; eventually resulting in closed chromatin (bottom right). After DNA replication, newly synthesized DNA (in green) is unmethylated. However, DNMT1 rapidly scans DNA and deposits methyl groups on newly synthesized DNA, opposite methyl groups present on the old DNA strand. This results in faithful replication of methylation patterns (bottom left) and the maintenance of silencing. Adult patterns of methylation are erased by epigenetic reprogramming in early embryogenesis (top left). * 1.The presence of methyl groups in the major groove interferes with the binding of transcription factors that activate transcription from a specific gene. 2. * * * Seven distinct mechanisms in combination can generate numerous structural and functional diversities for a single chromatin-remodelling complex. Transcription factors can target the complex for recruitment to specific target genes. The binding of structured DNA, such as three-way and four-way junctions that represent DNA replication and repair intermediates, can also recruit and potentially alter the activity of the complex. Small molecules, such as inositol polyphosphates and phosphoinositides, can modulate the activity of the complex. Additionally, subunits in the complex can be post-translationally modified or exchanged (swapped)119 to alter the function of the complex. The activity of specific subunits can also be regulated by transient association of the complex with activating factors, such as the activation of the deubiquitylating enzyme ubiquitin c