Epigenetische Kontrolle des Cytomegalievirus-Chromosoms
Final Report Abstract
Human cytomegalovirus (CMV), one of eight human herpesviruses, establishes life-long infections in most of us. CMV has long been known for causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals, but preventive and therapeutic options are still very limited. The large double-stranded DNA genomes of all herpesviruses are transcribed, replicated and encapsidated in the host cell nucleus, where DNA is typically structured and maneuvred through nucleosomes. Nucleosomes individually assemble DNA around core histone octamers to form chromatin fibres. Herpesvirus DNA is devoid of histones within virion capsids. Following release into the nucleus, however, viral genomes undergo rapid nucleosome assembly by replication‐independent mechanisms, and nucleosomes occupy nuclear viral DNA in a non-random and highly predictable fashion. At early times of infection, nucleosomes associate with the CMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, viral DNA is subject to replication-dependent nucleosome assembly, and nucleosomes redistribute extensively to establish patterns mostly determined by non-genetic factors. We propose that these factors include key regulators of viral gene expression encoded at the CMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with wild-type genomes. The temporal nucleosome occupancy differences between IE1-deficient and wild-type viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. Concurrent with the changes in nucleosome occupancy, histone modifications across the CMV genome globally change from a heterochromatin- to a euchromatin-like pattern as infection proceeds from early to late. Finally, our work defines in detail the structural basis for chromatin binding by the CMV IE1 protein. IE1 exhibits two distinct core histone binding domains, one of which (the chromatin tethering domain) targets the ‘acidic pocket’ on the nucleosome surface in a nucleic acid-independent fashion. These results provide a framework of spatial and temporal nucleosome organization and modification across the genome of a major human pathogen and suggest that a CMV major IE protein governs overall viral chromatin structure and function to regulate transcription. Exploiting chromatin targets for novel anti-viral treatment strategies may help to combat the massive health-related and economic burdens associated with CMV. Epigenie (25.07.2013): http://epigenie.com/epigenetics-goes-viral-herpes-the-histone-hijacker Science Daily (30.07.2013): http://75.101.140.165/releases/2013/07/130730163148.htm Bioscience Technology (31.07.2013): http://www.biosciencetechnology.com/news/2013/07/learning-herpes-virus Today Topics (01.08.2013): http://www.todaytopics.com/how-cells-regulate-the-human-cytomegalovirus-themechanism-by-which-genetic-information-is-packaged-and-stored/14294 Mideast Clinics Directory (01.08.2013): http://www.mideastclinics.com/healthNews/19729/GW7/How-cells-regulate-the-humancytomegalovirus%3A-the-mechanism-by-which-genetic-information-is-packaged-andstored.html#.UywCtFea81w Vaccine News Daily (01.08.2013): http://vaccinenewsdaily.com/medical_countermeasures/326395-researchers-learn-howherpes-virus-stores-information Glanzlicht Biomedizinischer Forschung (01.02.2014): http://www.ukr.de/wissenschaftler/Highlight/Februar_2014_Glanzlicht/index.php
Publications
- Epigenetische Kontrolle der Cytomegalievirus-Infektion. Kumulative Habilitationsschrift zur Erlangung der Lehrbefähigung im Fach Medizinische Mikrobiologie. University of Regensburg. 2008
Nevels M
- Temporal dynamics of cytomegalovirus chromatin assembly in productively infected human cells. J Virol. 2008 Nov; 82(22):11167-80
Nitzsche A, Paulus C, Nevels M
- Activation of telomerase in glioma cells by human cytomegalovirus: another piece of the puzzle. J Natl Cancer Inst. 2009 Apr 1;101(7):441-3
Cinatl J Jr, Nevels M, Paulus C, Michaelis M
- The human cytomegalovirus major immediate-early proteins as antagonists of intrinsic and innate antiviral host responses. Viruses 2009 Nov;1(3):760-79
Paulus C, Nevels M
- Chromatinisation of herpesvirus genomes. Rev Med Virol. 2010 Jan;20(1):34-50
Paulus C, Nitzsche A, Nevels M
- How to control an infectious bead string: nucleosomebased regulation and targeting of herpesvirus chromatin. Rev Med Virol. 2011 May;21(3):154-80
Nevels M, Nitzsche A, Paulus C
- Histone H3 lysine 4 methylation marks postreplicative human cytomegalovirus chromatin. J Virol. 2012 Sep;86(18):9817-27
Nitzsche A, Steinhäußer C, Mücke K, Paulus C, Nevels M
(See online at https://doi.org/10.1128/JVI.00581-12) - Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein. Proc Natl Acad Sci USA. 2013 Aug 6;110(32):13126-31
Zalckvar E, Paulus C, Tillo D, Asbach-Nitzsche A, Lubling Y, Winterling C, Strieder N, Mücke K, Goodrum F, Segal E, Nevels M
(See online at https://doi.org/10.1073/pnas.1305548110) - Snapshots: Chromatin control of viral infection. Virology. 2013 Jan 5;435(1):141-56
Knipe DM, Lieberman PM, Jung JU, McBride AA, Morris KV, Ott M, Margolis D, Nieto A, Nevels M, Parks RJ, Kristie TM
(See online at https://doi.org/10.1016/j.virol.2012.09.023) - Human cytomegalovirus major immediate-early 1 protein targets host chromosomes by docking to the acidic pocket on the nucleosome surface. J Virol. 2014 Jan;88(2):1228-48
Mücke K, Paulus C, Bernhardt K, Gerrer K, Fink A, Schön K, Fink A, Sauer EM, Asbach- Nitzsche A, Harwardt T, Kieninger B, Kremer W, Kalbitzer HR, Nevels M
(See online at https://doi.org/10.1128/JVI.02606-13)
