Splicing factor 3B1 hypomethylation is associated with altered SF3B1 transcript expression in older humans.
Ageing in man is associated with changes to the splicing factor pool. A proportion of splicing factors are regulated during ageing by mechanisms involving the Ataxia Telangiectasia Mutated (ATM) gene, but the factors that determine the remaining proportion have yet to be identified. DNA methylation is known to be an important regulatory mechanism of gene expression. We assessed age-associated methylation and expression levels for 27 splicing factor genes, in peripheral blood samples from the InCHIANTI study. Examination of splicing patterns at specific loci was examined in a second cohort, the Exeter 10000 study. 27/502 methylation probes in 17 different genes were associated with age. Most changes were not associated with transcript expression levels or splicing patterns, but hypomethylation of the SF3B1 promoter region was found to mediate 53% of the relationship between age and transcript expression at this locus (p=0.02). DNA methylation does not appear to play a major role in regulation of the splicing factors, but changes in SF3B1 expression may be attributable to promoter hypomethylation at this locus. SF3B1 encodes a critical component of the U2 snRNP; altered expression of this gene may therefore contribute to the loss of regulated mRNA splicing that occurs with age.
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
Alice C
AC
Holly
Epidemiology and Public Health, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
Luke C
LC
Pilling
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
Dena
D
Hernandez
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
Benjamin P
BP
Lee
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
Andrew
A
Singleton
National Institute on Aging, Clinical Research Branch, Harbor Hospital, Baltimore, MD 21225, USA.
Luigi
L
Ferrucci
Epidemiology and Public Health, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
David
D
Melzer
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK. Electronic address: L.W.Harries@exeter.ac.uk.
Lorna W
LW
Harries
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D015331:Cohort Studies; D004247:DNA; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D004247:DNA
Ageing; DNA methylation; Epigenetics; SF3B1; Splicing