Dataset Information

Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.

ABSTRACT: 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.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.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).Gene expression and DNA methylation changes in aneurysmal subarachnoid hemorrhage patients undergoing RIC are involved in coordinated cell cycle and inflammatory responses.

SUBMITTER: Nikkola E

PROVIDER: S-EPMC4550559 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.

Nikkola Elina E Laiwalla Azim A Ko Arthur A Alvarez Marcus M Connolly Mark M Ooi Yinn Cher YC Hsu William W Bui Alex A Pajukanta Päivi P Gonzalez Nestor R NR

Stroke 20150806 9

<h4>Background and purpose</h4>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.<h4>Methods</h4>Thirteen patients underwent 4 RIC sessions over 2 to 12 days after rupture of an intra ...[more]

PMID: 26251247

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Project description:Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

Project description:Subarachnoid hemorrhage (SAH) is a major cause of death and morbidity worldwide, often due to rupture of intracranial aneurysms (IAs). Immune infiltration and inflammatory activation play key roles in the process of aneurysmal SAH (aSAH). This study aimed to elaborate the immune infiltration and identify related biomarkers both in blood and tissue samples from patients with aSAH. Expression data of aSAH and healthy control samples were obtained from gene expression omnibus (GEO) database. Overall, a blood sample dataset GSE36791 and a tissue sample dataset GSE122897 were included. Differentially expressed genes (DEGs) between aSAH and healthy samples were explored. We applied GO biological and Gene Set Enrichment Analyses (GSEA) processes to access the functional enrichment. Then feature elimination algorithms based on random forest were used to screen and verify the biomarkers of aSAH. We performed three computational algorithms including Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), Microenvironment Cell Populations-counter (MCPcounter), and xcell to evaluate the immune cell infiltration landscape to identify the unique infiltration characteristics associated with rupturing. We found 2,220 DEGs (856 upregulated and 1,364 downregulated) in the original dataset. Functional analysis revealed most of these genes are enriched in immunological process, especially related with neutrophil response. Similar signaling pathway enrichment patterns were observed in tissue sample dataset and ClueGo. Analysis of immune microenvironment infiltration suggested neutrophils were abnormally upregulated in aSAH compared with those in the control group. Key gene SRPK1 was then filtered based on feature elimination algorithms, and transcription factor (TF) ZNF281 is assumed to participate in immunomodulation by regulating expression of SRPK1. Several immunomodulators such as CXCR1 and CXCR2 also appear to be involved in the progression of aSAH. In the present study, we performed a comprehensive stratification and quantification of the immune infiltration status of aSAH. By exploring the potential mechanism for aSAH based on several computational algorithms, key genes including SRPK1 and ZNF281 were filtered. This study may be of benefit to patients who are at high risk of suffering aSAH which allows for early diagnosis and potential therapy.

Project description:Spontaneous Intracerebral hemorrhage (ICH) is a devastating injury that accounts for 10-15% of all strokes. The rupture of cerebral blood vessels damaged by hypertension or cerebral amyloid angiopathy creates a space-occupying hematoma that contributes toward neurological deterioration and high patient morbidity and mortality. Numerous protocols have explored a role for surgical decompression of ICH via craniotomy, stereotactic guided endoscopy, and minimally invasive catheter/tube evacuation. Studies including, but not limited to, STICH, STICH-II, MISTIE, MISTIE-II, MISTIE-III, ENRICH, and ICES have all shown that, in certain limited patient populations, evacuation can be done safely and mortality can be decreased, but functional outcomes remain statistically no different compared to medical management alone. Only 10-15% of patients with ICH are surgical candidates based on clot location, medical comorbidities, and limitations regarding early surgical intervention. To date, no clearly effective treatment options are available to improve ICH outcomes, leaving medical and supportive management as the standard of care. We recently identified that remote ischemic conditioning (RIC), the non-invasive, repetitive inflation-deflation of a blood pressure cuff on a limb, non-invasively enhanced hematoma resolution and improved neurological outcomes via anti-inflammatory macrophage polarization in pre-clinical ICH models. Herein, we propose a pilot, placebo-controlled, open-label, randomized trial to test the hypothesis that RIC accelerates hematoma resorption and improves outcomes in ICH patients. Twenty ICH patients will be randomized to receive either mock conditioning or unilateral arm RIC (4 cycles × 5 min inflation/5 min deflation per cycle) beginning within 48 h of stroke onset and continuing twice daily for one week. All patients will receive standard medical care according to latest guidelines. The primary outcome will be the safety evaluation of unilateral RIC in ICH patients. Secondary outcomes will include hematoma volume/clot resorption rate and functional outcomes, as assessed by the modified Rankin Scale (mRS) at 1- and 3-months post-ICH. Additionally, blood will be collected for exploratory genomic analysis. This study will establish the feasibility and safety of RIC in acute ICH patients, providing a foundation for a larger, multi-center clinical trial.

Dataset Information

Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.

Publications

Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.

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