TY - JOUR
T1 - Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states
AU - Rodriguez-Algarra, Francisco
AU - Seaborne, Robert A.E.
AU - Danson, Amy F.
AU - Yildizoglu, Selin
AU - Yoshikawa, Harunori
AU - Law, Pui Pik
AU - Ahmad, Zakaryya
AU - Maudsley, Victoria A.
AU - Brew, Ama
AU - Holmes, Nadine
AU - Ochôa, Mateus
AU - Hodgkinson, Alan
AU - Marzi, Sarah J.
AU - Pradeepa, Madapura M.
AU - Loose, Matthew
AU - Holland, Michelle L.
AU - Rakyan, Vardhman K.
N1 - Funding Information:
Biotechnology and Biological Sciences Research Council grant BB/G00711X/1 (VKR); Biotechnology and Biological Sciences Research Council grant BB/R00675X/1 (FRA, RAES, VKR); The Barts Charity Research grant MGU0390 (VKR); Rosetrees PhD studentship A1903 to SY (VKR); Biotechnology and Biological Sciences Research Council LIDO studentship BB/M009513/1 (ZA); Academy of Medical Sciences award SBF003\1026 (MLH); Edmond and Lily Safra Research Fellowship (SJM); Royal Society Research Grant RGS\R2\180202 (MLH); MRC grant MR/T000783/1 (MMP); The Barts Charity Research grant MGU0475 (MMP); The Wellcome Trust grant 204843/Z/16/Z, (NH, ML); JSPS KAKENHI 21K06138 (HY).
Funding Information:
We thank Profs Sue Ozanne and Oliver Rando for feedback on the work, Dr Miguel Branco for the H3K9me3 Ab, and Dr Pankaj Dubey for help in CUT&Tag-seq library preparation. We also thank The Bart’s and the London Genome Centre for sequencing and the assistance of the ITS Research team at Queen Mary University of London. This manuscript was previously reviewed at another journal and no review history is available. Stephanie McClelland and Anahita Bishop were the primary editors of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2/14
Y1 - 2022/2/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124584079&partnerID=8YFLogxK
U2 - 10.1186/s13059-022-02617-x
DO - 10.1186/s13059-022-02617-x
M3 - Article
C2 - 35164830
AN - SCOPUS:85124584079
SN - 1474-760X
VL - 23
SP - 54
JO - Genome Biology
JF - Genome Biology
IS - 1
M1 - 54
ER -