title: Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.
abstract: OBJECTIVE
  Remote ischemic conditioning (RIC) is a phenomenon in which short periods of nonfatal ischemia in 1 tissue confers protection to distant tissues. Here we performed a longitudinal human pilot study in patients with aneurysmal subarachnoid hemorrhage undergoing RIC by limb ischemia to compare changes in DNA methylation and transcriptome profiles before and after RIC.
  
  
  METHODS
  Thirteen patients underwent 4 RIC sessions over 2 to 12 days after rupture of an intracranial aneurysm. We analyzed whole blood transcriptomes using RNA sequencing and genome-wide DNA methylomes using reduced representation bisulfite sequencing, both before and after RIC. We tested differential expression and differential methylation using an intraindividual paired study design and then overlapped the differential expression and differential methylation results for analyses of functional categories and protein-protein interactions.
  
  
  RESULTS
  We observed 164 differential expression genes and 3493 differential methylation CpG sites after RIC, of which 204 CpG sites overlapped with 103 genes, enriched for pathways of cell cycle (P<3.8×10(-4)) and inflammatory responses (P<1.4×10(-4)). The cell cycle pathway genes form a significant protein-protein interaction network of tightly coexpressed genes (P<0.00001).
  
  
  CONCLUSIONS
  Gene expression and DNA methylation changes in aneurysmal subarachnoid hemorrhage patients undergoing RIC are involved in coordinated cell cycle and inflammatory responses.
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Azim
authors.initials: A
authors.lastname: Laiwalla
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Mark
authors.initials: M
authors.lastname: Connolly
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Yinn Cher
authors.initials: YC
authors.lastname: Ooi
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: William
authors.initials: W
authors.lastname: Hsu
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Alex
authors.initials: A
authors.lastname: Bui
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.).
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.affiliation: From the Department of Human Genetics (E.N., A.K., M.A., P.P.), Department of Neurosurgery (A.L., M.C., Y.C.O., N.R.G.), and Department of Radiological Sciences (W.H., A.B., N.R.G.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Human Genetics and Molecular Biology, Molecular Biology Institute at UCLA, Los Angeles, CA (A.K., P.P.). ngonzalez@mednet.ucla.edu.
authors.forename: Nestor R
authors.initials: NR
authors.lastname: Gonzalez
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D002532:Intracranial Aneurysm / Q000378:metabolism* / Q000628:therapy; D019194:Ischemic Preconditioning / Q000379:methods*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000628:therapy; D059467:Transcriptome / Q000502:physiology
keywords: DNA methylation; aneurysm; genomics; preconditioning; subarachnoid hemorrhage; transcriptome