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4 Histone Code, Modifications, Remodelling Epicourse 2012 Histone code hypothesis Epigenetics 2012 by Nigel Atkinson From Chapter 13 Weaver The University of Texas at Austin Chromatin Structure and its Effects on Transcription continued Idea of the histone code • The combination of histone modifications on a given nucleosome affects efficiency of transcription of the gene. How many characters are there in this code? • More than 100 modifications have been detected by NMR. • Many scientists find this to be disquieting because you can make a huge number of unique patterns (code words) with a 100 character alphabet. • Modifications in one histone can affect (allow or prevent) a modification in an another histone. human interferon-beta gene (IFN-ß) • Dimitris Thanos • human interferon-beta gene (IFN-ß) • viral infection activates it. • TF activators bind nucleosome free areas near promoter generating an enhanceosome. Histone code hypothesis/model Kinase binds enhanceosome & phosphoryaltes H3 S10. NOW GCN 5 can acetylate H3 K14. enhanceosome Histone code is complete & now proteins use it. Acetylated H4K8 is recognized enhanceosome recruits GCN5 by SWI/SNF. SWI/SNF remodels nucleosome. The GCN5 HAT acetylates H4 K8 & K3 K9 TFIID is attracted by acetylated H3 K9 and H3 K14. Nucleosome now lets TFIID have access to the TATA box. which it binds. Then it bends the DNA and the nucleosome moves. The ChIP assay chromatin immunoprecipitation • Allows one to determine which proteins and molecules are present on a transcriptional control region. • Allows one to detect changes in abundance of proteins and molecules on a transcriptional control region. Decoding the Histone Acetylation Code Agalioti383 et al 2002 Laboratory of Dimitris Thanos Time course of Sendai virus infection of HeLa cells. Weaver Fig 13.30 4th ed. Figure 1. Virus Infection Induces a Distinct Pattern of Histone Acetylation at the IFN-␤ Promoter In Vivo (A) HeLa cells were either mock- or virus-infected with Sendai virus for the indicated amounts of time. Cross-linked chromatin was immunopre- cipitated with the indicated antibodies and the IFN-␤ promoter was detected by PCR in these samples using promoter-specific primers. The bottom part of the figure shows the abundance of the IFN-␤ mRNA as detected by RT-PCR. (B) Cross-linked chromatin precipitated with the histone H4 (K5, K8, K12, and K16), H4 (K5), and H4 (K16) acetylation-specific antibodies (lane 1), or beads (lane 2) was separated by SDS PAGE along with input chromatin (lane 3) followed by Western blot using the same antibodies as immunoprobes as indicated in the figure. (C) The IFN-␤ enhanceosome was assembled on a biotinylated promoter fragment (Ϫ143 to ϩ183) bearing the nucleosome (Ϫ15 to ϩ132) followed by incubation with HeLa nuclear extracts in the absence (lanes 1 and 2) or the presence of Acetyl-CoA. The proteins were analyzed by SDS PAGE and specifically acetylated histone lysine residues were detected by Western blotting using the antibodies shown on the left part of the figure. (D) Same as in (C) except the templates were incubated either with complete nuclear extracts (lanes 1 and 2), CBP/p300 depleted extracts (lanes 3 and 4), GCN5/PCAF depleted extracts (lanes 5 and 6), or BRG1/BRM depleted extracts (lanes 7 and 8) followed by Western blot analysis using an antibody that recognizes specifically acetylated H4K8. (E) Shown is a Western blot using the indicated antibodies (shown on the left) and either complete (lanes 1, 3, and 5), or CBP/p300-depleted (lane 2), or GCN5/PCAF-depleted (lane 4) or SWI/SNF-depleted-HeLa nuclear extracts (lane 6). to occur (Agalioti et al., 2000). The acetylated lysine of CBP/p300 did not affect histone acetylation (lanes 3 residues in histones H3 and H4 were detected by West- and 4). As a control, we showed that depletion of the ern blot analysis using specific antibodies. In agreement SWI/SNF complex did not affect the pattern of histone with the in vivo results (Figure 1A), the enhanceosome acetylation (lanes 7 and 8). The Western blot of Figure recruits HAT proteins in vitro, which acetylate H4 and 1E shows that removal of GCN5/PCAF from the extracts H3 at K8 and K14 (and K9, data not shown), respectively. did not lead to codepletion of CBP and that depletion Thus, both in vivo and in vitro, the enhanceosome in- of CBP did not lead to depletion of GCN5/PCAF. These duces acetylation of histones H3 and H4 at the same experiments suggest that GCN5 is the primary histone residues. To determine which of the HAT proteins re- acetylase that functions in the site-specific acetylation cruited by the enhanceosome causes site-specific acet- of the nucleosome at the IFN-␤ promoter. This conclu- ylation, we repeated the above experiment using ex- sion is consistent with the observation that histone acet- tracts depleted for GCN5/PCAF or CBP/p300. Figure 1D ylation at the IFN-␤ promoter in vivo correlates better shows that depletion of GCN5/PCAF abolishes H4 K8 with the recruitment of GCN5 than with that of CBP (and H3 K14, data not shown) acetylation in vitro (com- during the time course of virus infection (Agalioti et al., pare lanes 1 and 2 with 5 and 6). Surprisingly, depletion 2000, Lomvardas and Thanos, 2002). Early evidence that the histone modifications can be read in as combinations of letters. Histone methylation in Drosophila pg 392 Weaver 4th ed. methyl lys4 lys9 • Repressed H2N H3 lys20 H2N H4 Repressors HP1 & polycomb can bind. methyl methyl lys4 lys9 H2N methyl H3 lys20 • Stimulated H2N H4 Now can be bound by the activator Brahma but not by the repressors HP1 and polycomb. Interpreted to mean that the proteins are interpreting a code. Methylated K9 has a diferent meaning when it is in the presence of methylated K4 and methylated K20. End REVIEWS a Histone tail Overview of epigenetic mechanisms Chromatin is the complex of DNA, histones and non- histone proteins in the cell nucleus. Remodelling of chromatin is a dynamic process that modulates gene expression. The fundamental unit of chromatin is the DNA nucleosome, which consists of ~147 base pairs of DNA H2B wrapped around a core histone octamer (~1.65 turns). H4 Each octamer contains two copies each of the histones H2A, H2B, H3 and H4 (FIG. 1a). The nucleosomal struc- H3 ture of chromatin allows DNA to be tightly packaged H2A into the nucleus by organized folding5. Intricate chroma- tin remodelling mechanisms ensure that DNA remains accessible to the transcriptional machinery. These A Acetylation epigenetic mechanisms alter gene activity by modulat- Histone M Methylation ing DNA–protein interactions without changing the genetic code. b Active P Phosphorylation In simplified terms, chromatin exists in an inac- Histone Histones Transcription factor Permissive tivated, condensed state, heterochromatin, which does tail + not allow transcription of genes, and in an activated, A A A M M P A A open state, euchromatin, which allows individual genes to be transcribed (FIG. 1b). The opening of chroma- tin is associated with acetylation of nearby histones, although it remains unclear whether acetylation A mediates or reflects chromatin decondensation. In A M Co-Act A A M reality, chromatin can exist in many states in between DNA Basal transcription complex Inactive Figure 1 | General scheme of chromatin remodelling. M M P P a | Picture of a nucleosome showing a DNA strand wrapped Repressed around a histone octamer composed of two copies each of Rep Rep the histones H2A, H2B, H3 and H4. The amino (N) termini of M Rep the histones face outward from the nucleosome complex. M M M M Rep A M M b | Chromatin can be conceptualized as existing in two Rep A M primary structural states: as active, or open, euchromatin M (top left) in which histone acetylation (A) is associated ? M with opening the nucleosome to allow binding of the B) It's memory! basal transcriptional complex and other activators of Rep M Maintenance of the modification M M transcription; or as inactive, or condensed, Acetylation M heterochromatin where all gene activity is permanently M M Propagation of the modification silenced (bottom left). In reality, chromatin exists in a Methylation and X-chromosome inactivation c continuum of several functional states (active; permissive Demethylation Demethylation (top right); repressed (bottom right); and inactive). Enrichment of histone modifications such as acetylation and methylation (M) at histone N-terminal tails and related HDMHMT HDM HMT binding of transcription factors and co-activators (Co-Act) or repressors (Rep) to chromatin modulates the Methylation Methylation transcriptional state of the nucleosome. Recent evidence (activating) (repressing) suggests that inactivated chromatin may in some cases be subject to reactivation in adult nerve cells, although this remains uncertain. c | Summary of common covalent M M modifications of H3, which include acetylation, M M methylation and phosphorylation (P) at several amino acid H3 K4 K27 S M K 3 28 residues. H3 phosphoacetylation commonly involves 9 K2 K3 S 18 6 phosphorylation of S10 and acetylation of K14. Acetylation 10 K14 K P K79 A A is catalysed by histone acetyltransferases (HATs) and P A A Histone reversed by histone deacetylases (HDACs); lysine tail methylation (which can be either activating or repressing) Acetylation Phosphorylation is catalysed by histone methyltransferases (HMTs) and (activating) (activating) reversed by histone demethylases (HDMs); and phosphorylation is catalysed by protein kinases (PK) and HAT HDAC PK PP reversed by protein phosphatases (PP), which have not yet been identified with certainty. K, lysine residue; S, serine residue. Panels a,c modified, with permission, from Nature Deacetylation Dephosphorylation Rev. Neurosci. REF. 62 (2005) Macmillan Publishers Ltd. Tsankova, N, Renthal, W, Kumar, A, Nestler, EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci, 8:355–367. 356 | MAY 2007 | VOLUME 8 www.nature.com/reviews/neuro Extra for later • H3K9 recruits HP1 • HP1 has chromodom and showdow chromodomain (binds nucleosomes together) • binds Su(var)3Y9 histone methyl transferases (H3K9methylation) which triggers spreading..
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