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6 - Heterochromatin and epigenetic control of gene expression, Grewal & Moazed.doc

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David Rollo

Article 6 Heterochromatin and Epigenetic Control of Gene Expression Abstract -epigenetically heritable domains of heterochromatin: -control the structure and expression of large chromosome domains -are required for proper chromosome segregation -assembly process of chromosome domainsoccurs in steps: -has many rounds of of histone modification through silencing complexes that spread along the chromatin fibre by self-oligomerization and association with modified histone amino-terminal tails Introduction - folding of DNA in chromatin regulate processes such as gene expression and chromosome dynamics - local chromatin regulation is at a single gene, on the globla scale its at chromosome domains or the entire chromosome – can both at the nucleosome (the fundamental unit of chromosome folding) -heterochromatin aka ‘silent chromatin’ -chromosomes have 2 types of domains: 1) euchromatin 2) heterochromatin - -Heterochromatin domains: inaccessible by DNA binding factors and are transcriptionally silent -Euchromatin domains: accessible by DNA binding factors, and are transcriptionally active -large heterochromatin surrounds functional chromosome structures like centromeres and telomeres -small heterochromatin structures are found throughout the chromosome -CENTROMERES AND HETEROCHROMATIN: - heterochromatin plays a central role in centromere function -heterochromatin proteins are associated with DNA repeats that surround centromeres -heterochromatin also stabilizes repetitive DNA sequences at centromeres, telomeres, and elsewhere in the genome -through inhibiting recombination b/w homologous repeats -REGULATION OF GENE EXPRESSION: -heterochromatin-like structures are involved in the stable inactivation of developmental regulators (ie. homeotic gene clusters) -heterochromain inactivates one of the 2 ‘X’ chromosomes in female somatic cells -PROPERTIES OF HETEROCHROMATIN: -it is suitable for processes that require stable maintenance of expression states over long periods: 1) the heterochromatic state is epigenetically and stably inherited through many cell divisions 2) assembly and spreading of heterochromatin from its origin site to surrounding DNA regions allows transition from sequence specific genetic control to sequence-independent epigenetic control Factors in Heterochromatin Assembly -histones and their post-translational modifications play an important role in the assemble of heterochromatin -in eukaryotes: -DNA is assembeled with histones to form a nucleosome -DNA is wrapped about 2 turns around an 8-unit complex composed of 2 of each of H2A, H2B, H3, H4 -the amino-terminus of histones have many post-translational modifications: -acetylation methylation of lysine residues in the amino-termini of H3 and H4 -increased acetylation = correlates with transcriptional activity -decreased acetylation = correlates with transcriptional repression -therefore, heterochromatic state is assoc with HYPOacetylation of histones -many factors needed for heterochromatin assembly are: 1) enzymes that modify histones 2) factors that bind to histones -BUDDING YEAST: -products of the silent information regulator (SIR) genes Sir2, Sir3, and Sir4 are required for the assembly of heterochromatin -these are required at the ‘silent mating-type loci’ and ‘telomeric DNA regions’ -the Sir proteins form a complex -the Sir3 and 4 proteins can bind de-acetylated histone tains -the Sir2 protein is a NAD-dependent histone de-acetylase, its deacetylase activity is required for heterochromatin assembly HISTONE H3 LYSINE 9 (H3 Lys9): -methylation of H3 Lys9 correlates with heterochromatin assembly -it is methylated by methyltransferase -the methyltransferases are associated with Swi6 (yeast) of HP1 (human and drosophila) -Swi6/HP1 proteins bind to H3 Lys9 tails (=methylated at Lys9) -DNA METHYLATION: -contributes to stability of silenced chromatin - feedback mechanisms between DNA and histone methylation  one promotes maintenance of the other - DNA methylation and chromatin-mediated and epigenetic mechanisms act in concert to maintain a silenced chromatin state Role of Silencers, Repeats, and RNA’s in Nucleation of Heterochromatin -repetitive DNA elements and non-coding RNA’s are involved in regional targeting of heterochromatin complexes -transposons and satellite repeats (heterochromatin a lot) are involved in recruiting heterochromatin machinery to silence nearby genes -NON-CODING RNA’s: - play a role in regulation of chromosome beahviour - chromosome localization of chromatin-modifing activities (ie. for genomic imprinting) -Xist RNA is required for initiation of X-inactivation -silencing is also regulated by Tsix -association of rox RNA with MSL complex is imp for dosage compensation in drosophila -in plants, dsRNA can cause post-transcriptional and transcriptional silencing -RNA INTERFERENCE (RNAi) PATHWAY: -role in post-transcriptional gene silencing -also involved in initiating heterochromatin assembly at repetitive DNA -parts of RNAi machinery (ago1, der1, rdp1)are required for heterochromatin formation and targeting of H3 Lys9 methylation -centromeric repeat sequences that are transcribed at low levels are produce dsRNA can recruit heterochromatin, and recruitment is dependent on RNAi machinery -role of RN
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