Francisco Rodriguez-Algarra1, Robert A E Seaborne1, Amy F Danson1,2, Selin Yildizoglu1, Harunori Yoshikawa3, Pui Pik Law1,4, Zakaryya Ahmad1, Victoria A Maudsley1, Ama Brew1, Nadine Holmes5, Mateus Ochôa1, Alan Hodgkinson4, Sarah J Marzi6,7, Madapura M Pradeepa1, Matthew Loose5, Michelle L Holland8, Vardhman K Rakyan9. 1. The Blizard Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK. 2. Present Address: German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. 3. Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. 4. Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK. 5. DeepSeq, School of Life Sciences, University of Nottingham, Nottingham, UK. 6. UK Dementia Research Institute, Imperial College London, London, UK. 7. Department of Brain Sciences, Imperial College London, London, UK. 8. Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK. michelle.holland@kcl.ac.uk. 9. The Blizard Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK. v.rakyan@qmul.ac.uk.
Abstract
BACKGROUND: Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. RESULTS: Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. CONCLUSIONS: Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases.
BACKGROUND: Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. RESULTS: Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. CONCLUSIONS: Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases.
Authors: Daniel A Petkovich; Dmitriy I Podolskiy; Alexei V Lobanov; Sang-Goo Lee; Richard A Miller; Vadim N Gladyshev Journal: Cell Metab Date: 2017-04-04 Impact factor: 27.287
Authors: Jeremy M Shea; Ryan W Serra; Benjamin R Carone; Hennady P Shulha; Alper Kucukural; Michael J Ziller; Markus P Vallaster; Hongcang Gu; Andrew R Tapper; Paul D Gardner; Alexander Meissner; Manuel Garber; Oliver J Rando Journal: Dev Cell Date: 2015-12-21 Impact factor: 12.270
Authors: Paula Dominguez-Salas; Sophie E Moore; Maria S Baker; Andrew W Bergen; Sharon E Cox; Roger A Dyer; Anthony J Fulford; Yongtao Guan; Eleonora Laritsky; Matt J Silver; Gary E Swan; Steven H Zeisel; Sheila M Innis; Robert A Waterland; Andrew M Prentice; Branwen J Hennig Journal: Nat Commun Date: 2014-04-29 Impact factor: 14.919
Authors: Thomas Dahlet; Andrea Argüeso Lleida; Hala Al Adhami; Michael Dumas; Ambre Bender; Richard P Ngondo; Manon Tanguy; Judith Vallet; Ghislain Auclair; Anaïs F Bardet; Michael Weber Journal: Nat Commun Date: 2020-06-19 Impact factor: 14.919
Authors: Jeannine Diesch; Megan J Bywater; Elaine Sanij; Donald P Cameron; William Schierding; Natalie Brajanovski; Jinbae Son; Jirawas Sornkom; Nadine Hein; Maurits Evers; Richard B Pearson; Grant A McArthur; Austen R D Ganley; Justin M O'Sullivan; Ross D Hannan; Gretchen Poortinga Journal: Commun Biol Date: 2019-01-28