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Functional Characterization of CDY Family Proteins and Their Role in Recognition of the Heterochromatic Histone H3k9me3 Modification

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Functional Characterization of CDY Family Proteins and Their Role in Recognition of the Heterochromatic Histone H3k9me3 Modification Functional characterization of CDY family proteins and their role in recognition of the heterochromatic histone H3K9me3 modification Dissertation for the award of the degree ‘Doctor rerum naturalium’ (Dr. rer. nat.) Division of Mathematics and Natural Sciences of the Georg-August-University Göttingen submitted by Henriette Franz born in Jena November 2009 Thesis Supervisor: Dr. Wolfgang Fischle Doctoral Committee: Dr. Wolfgang Fischle (1st Referee) Chromatin Biochemisty, Max-Planck-Institute for biophysical Chemistry, Göttingen Prof. Dr. Herbert Jäckle (2nd Referee) Molecular developmental Biology, Max-Planck- Institute for biophysical Chemistry, Göttingen Prof. Dr. Sigrid Hoyer-Fender Developmental Biology, Georg-August-University, Göttingen Date of submission of thesis: 30. November 2009 Date of oral exam: 5. January 2010 Affidavit I hereby ensure that the thesis has been written independently and with no other sources and aids than quoted. Göttingen, …………………………. List of publications Franz H, Mosch K, Soeroes S, Urlaub H, Fischle W (2009) Multimerization and H3K9me3 binding is required for CDYL1b heterochromatin association. J Biol Chem. Epub Oct 5 Somel M, Franz H, Yan Z, Lorenc A, Guo S, Giger T, Kelso J, Nickel B, Dannemann M, Bahn S, Webster MJ, Weickert CS, Lachmann M, Pääbo S, Khaitovich P (2009) Transcriptional neoteny in the human brain. Proc Natl Acad Sci USA. 2009 Apr 7;106(14):5743-8. Epub Mar 23 Fischle W*, Franz H*, Jacobs SA, Allis CD, Khorasanizadeh S (2008) Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. J Biol Chem. Jul 11;283(28):19626-35 Epub May 1 Somel M, Creely H, Franz H, Mueller U, Lachmann M, Khaitovich P, Pääbo S (2008) Human and chimpanzee gene expression differences replicated in mice fed different diets. PLoS ONE. Jan 30;3(1):e1504 Khaitovich P, Tang K, Franz H, Kelso J, Hellmann I, Enard W, Lachmann M, Pääbo S (2006) Positive selection on gene expression in the human brain Curr Biol. May 23;16(10):R356-8. Khaitovich* P, Kelso* J, Franz* H, Visagie J, Giger T, Joerchel S, Green RE, Lachmann M, Pääbo S (2006) Functionality of Intergenic Transcription: An Evolutionary Comparison. PLOS Genetics, Oct 13; 2(10) Khaitovich P, Hellmann I, Enard W, Nowick K, Leinweber M, Franz H, Weiss G, Lachmann M, Pääbo S (2005) Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science Sep 16, 309(5742): 1850-4 Franz H, Ullmann C, Becker A, Ryan M, Bahn S, Arendt T, Pääbo S, Khaitovich P (2005) Gene expression profiles in human brains before and after death. Genome Biology Dec 30; 6(13): R112 * equally contributed Contents 1 Introduction ....................................................................................................................1 1.1 Chromatin..................................................................................................................1 1.1.1 Histones and nucleosomes...................................................................................2 1.1.2 Chromatin as genomic regulator..........................................................................4 1.1.3 Chromatin modifications.....................................................................................4 1.1.4 Histone modifying enzymes ................................................................................6 1.1.5 Translating a histone mark...................................................................................7 1.1.6 Histone modification distribution along genomic regions ....................................9 1.1.7 Cross-talk between histone modifications..........................................................11 1.1.8 Histone H3 lysine 9 methylation........................................................................12 1.2 CDY family of proteins............................................................................................15 1.2.1 Identification of the CDY family.......................................................................15 1.2.2 Evolutionary aspects of the CDY family............................................................16 1.2.3 Domain structure of CDY family proteins .........................................................17 1.2.4 Splicing variants of CDYL1 ..............................................................................22 1.2.5 Interaction partners of CDY family proteins......................................................22 1.2.6 Biological impact of CDY family proteins.........................................................23 1.3 Open questions ........................................................................................................24 2 List of publications .......................................................................................................26 3 Specificity of the chromodomain Y chromosome family of chromodomains for lysine methylated ARK(S/T) motifs .............................................................................................27 4 Multimerization and H3K9me3 binding is required for CDYL1b heterochromatin association...........................................................................................................................28 5 Additional results..........................................................................................................29 5.1 CDYL1b function at heterochromatin ......................................................................29 5.1.1 CDYL1b expression has no influence on histone modifications.........................29 5.1.2 CDYL1 has at least two repressive activities .....................................................31 5.2 CDYL1b regulation .................................................................................................32 5.2.1 CDYL1b is displaced from chromatin during mitosis ........................................32 I 5.2.2 CDYL1b associates with the nuclear membrane/matrix.....................................34 5.3 CDYL1b is a substrate of PRMT5............................................................................37 5.3.1 Identification of PRMT5 as interaction partner of CDYL1b...............................37 5.3.2 PRMT5 methylates CDYL1b R80 in vitro.........................................................39 5.3.3 CDYL1b R80 methylation has only a minor effect on transcriptional repression42 5.4 Function of CDYL1b during Xenpous laevis development .......................................43 5.4.1 Expression of CDYL1b during Xenopus laevis development .............................43 5.4.2 CDYL1b overexpression in Xenopus laevis embryos.........................................44 5.4.3 Knock down of CDYL1b during development...................................................45 6 General discussion ........................................................................................................48 6.1 Chromodomains of CDY family members ...............................................................48 6.1.1 Chromodomains of CDY family proteins bind to H3K9me3..............................48 6.1.2 Chromodomain differences within splicing variants ..........................................49 6.1.3 Chromodomain binding to non-histone targets ..................................................50 6.1.4 Regulation of CDY family chromodomain binding to H3K9me2/me3...............50 6.2 ECH domains of CDY family proteins.....................................................................51 6.2.1 Functionality of the ECH domain of CDY family proteins.................................51 6.2.2 Multimerization of ECH domain .......................................................................52 6.3 Regulation of CDY family proteins..........................................................................53 6.3.1 Regulation by expression, splicing events or by splicing variants ......................53 6.3.2 Sequestration to nuclear membranes..................................................................54 6.3.3 Posttranslational modifications..........................................................................55 6.4 Function of CDY family proteins.............................................................................57 6.4.1 Repressive function...........................................................................................57 6.4.2 Putative developmental function of CDYL1b ....................................................58 6.4.3 Hypothetical function of CDYL1b in establishment and maintenance of heterochromatin............................................................................................................59 7 Supplemental material and methods to chapter 5.......................................................62 7.1 Materials..................................................................................................................62 7.1.1 Chemicals .........................................................................................................62 7.1.2 Buffers and media .............................................................................................64 II 7.1.3 Antibodies.........................................................................................................66 7.1.4 Kits ...................................................................................................................67 7.1.5 Enzymes............................................................................................................67 7.1.6 Primers and
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