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Non-Canonical Roles of Mammalian Heterochromatin Protein 1 (HP1) Homologs

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Non-Canonical Roles of Mammalian Heterochromatin Protein 1 (HP1) Homologs Non-canonical roles of mammalian heterochromatin protein 1 (HP1) homologs Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Veronika Ostapcuk aus der Tschechischen Republik Basel, 2018 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Marc Bühler und Prof. Dr. Wolf Reik. Basel, den 14. November 2017 Prof. Dr. Martin Spiess Dekan “When I was twelve, one of my friends bet another friend a bag of sweets that I would never come to anything. I don't know if this bet was ever settled, and if so, which way it was decided." Stephen Hawking Table of contents Summary ........................................................................................................................ 7 Introduction ............................................................................................................... 11 1. Milestones in the history of chromatin biology ....................................................... 12 2. Chromatin – structure and function......................................................................... 15 2.1. Histone variants .................................................................................................... 18 2.2. Histone modifications .......................................................................................... 19 2.2.1. Histone acetylation ......................................................................................................... 21 2.2.2. Histone phosphorylation ................................................................................................. 22 2.2.3. Histone methylation ........................................................................................................ 22 2.3. Distribution of distinct histone marks .................................................................. 24 3. Transcription factors ................................................................................................. 27 3.1. Activity dependent-neuroprotective protein ......................................................... 29 3.1.1. Domain organization ...................................................................................................... 29 3.1.2. Interacting partners ......................................................................................................... 30 3.1.3. Activity ........................................................................................................................... 31 4. Chromatin remodellers .............................................................................................. 32 5. Chromatin readers - HP1 proteins ........................................................................... 35 5.1. Domain organization ............................................................................................ 35 5.2. Interacting partners ............................................................................................... 37 5.3. Role of mammalian HP1s .................................................................................... 39 Results ............................................................................................................................ 43 1. H3K9me-independent targeting of mammalian HP1 homologs ............................ 44 1.1. RNA binding properties of mammalian HP1 homologs ...................................... 45 1.1.1. Introduction .................................................................................................................... 45 1.1.2. Objective ........................................................................................................................ 47 1.1.3. Results ............................................................................................................................ 48 1.1.4. Collaborations ................................................................................................................. 55 1.1.5. Methods .......................................................................................................................... 55 1.2. Transcription factor-mediated recruitment of the HP1 proteins to euchromatin . 56 1.2.1. Collaborations ................................................................................................................. 59 Discussion and Outlook .................................................................................... 61 5 1. H3K9-methylation dependent recruitment of HP1s ............................................... 63 1.1. Contributions of HP1 domains in mediating the H3K9me interaction ................ 63 1.2. Interdependency of HP1 and HKMTases ............................................................. 64 1.3. Mammalian HP1 homologs .................................................................................. 65 1.3.1. Redundancy of mammalian HP1 homologs in mouse ES cells ...................................... 66 2. RNA-mediated regulation of HP1 binding to chromatin........................................ 69 2.1. Sequence divergence of Swi6 and HP1 predicts different RNA-binding properties .......................................................................................................................... 69 2.2. Regulation of HP1 nucleic acid binding by PTMs ............................................ 70 2.3. HP1 binding to nucleosomes promotes RNA interaction and phase separation 72 2.4. Outlook ................................................................................................................. 74 3. DNA-sequence-dependent recruitment of HP1s ...................................................... 75 3.1. Identification of potential HP1 targeting factors .................................................. 76 3.2. Adnp-mediated recruitment of HP1s to euchromatin........................................... 77 3.2.1. Silencing mechanism of the ChAHP complex ................................................................ 78 3.3. Adnp2 as a prospective targeting factor of HP1s ................................................. 79 3.3.1. Potential redundancy of Adnp homologs and the existence of ChAHP2 ........................ 80 3.4. Mga as a prospective recruiter of HP1s ............................................................... 82 4. Concluding remarks ................................................................................................... 84 4.1. RNA-regulated binding of HP1 to pericentric chromatin .................................. 84 4.2. DNA-sequence-specific targeting of HP1s to silent euchromatin ........................ 86 References ................................................................................................................... 89 Acknowledgements .............................................................................................. 107 Appendix ..................................................................................................................... 110 6 Summary Summary 7 Summary The human body is composed of hundreds of different tissues, all containing same genetic information, yet defined by unique gene expression patterns. In order to achieve this, multicellular organisms evolved regulatory mechanisms that go beyond the mere DNA sequence. Unlike in prokaryotes, where DNA is freely accessible to the transcriptional machinery, DNA in eukaryotic cells is wrapped around histone proteins, forming a structure called chromatin. Importantly, chromatin can be regulated by various post-translational modifications of the histone proteins. Such modifications are generally assumed to directly affect the compaction of chromatin and/or act as a recruitment platform for chromatin factors that relax (activate) or condense (repress) chromatin. One of the repressive histone marks, histone 3 lysine 9 methylation (H3K9me), is recognised by members of the HP1 family and/or by other proteins that have the unique ability to spread along chromatin, compacting it, and ultimately forming large inaccessible domains referred to as heterochromatin. Over the past decade, however, the view of HP1s as rigid silencers has been gradually challenged, as it was found that heterochromatic regions produce RNA, and that HP1s are highly mobile molecules. In addition, HP1 proteins were shown to associate with RNAs, and to also associate with chromatin lacking the H3K9me mark. These findings raised several fundamental questions: Is HP1 activity regulated by RNA? How are HP1 proteins recruited to sites lacking H3K9me, and what is their role at those sites? One aim of my PhD project was to elucidate potential roles of RNA in modulating HP1 activity. For this, I used biochemical methods to dissect RNA binding properties of mammalian HP1 proteins in vitro. My work revealed that one of the HP1 homologs, HP1, interacts with RNA when bound to H3K9me-marked nucleosomes. The physiological role of such interaction could be stabilisation of binding to heterochromatin, or alternatively, eviction from heterochromatin. The major goal of my PhD project, however, was to investigate the mechanism of HP1 recruitment to chromatin lacking the H3K9me mark. To do so, I was using mouse embryonic stem cells (mESCs) as a model system. I have exploited recent advances in genome editing/CRISPR-Cas9 to delete or endogenously tag individual
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