Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

DCM_Titin_human_v1

ABSTRACT: RNA-Seq analysis of human Titin sequence variation and gene expression in DCM patients. The provided data files contain information for reads that map to human Titin only.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Oliver Hummel

PROVIDER: E-MTAB-2466 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts Angharad M AM Ware James S JS Herman Daniel S DS Schafer Sebastian S Baksi John J Bick Alexander G AG Buchan Rachel J RJ Walsh Roddy R John Shibu S Wilkinson Samuel S Mazzarotto Francesco F Felkin Leanne E LE Gong Sungsam S MacArthur Jacqueline A L JA Cunningham Fiona F Flannick Jason J Gabriel Stacey B SB Altshuler David M DM Macdonald Peter S PS Heinig Matthias M Keogh Anne M AM Hayward Christopher S CS Banner Nicholas R NR Pennell Dudley J DJ O'Regan Declan P DP San Tan Ru TR de Marvao Antonio A Dawes Timothy J W TJ Gulati Ankur A Birks Emma J EJ Yacoub Magdi H MH Radke Michael M Gotthardt Michael M Wilson James G JG O'Donnell Christopher J CJ Prasad Sanjay K SK Barton Paul J R PJ Fatkin Diane D Hubner Norbert N Seidman Jonathan G JG Seidman Christine E CE Cook Stuart A SA

Science translational medicine 20150101 270

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effec ...[more]

PMID: 25589632

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Project description:There is a ever widening gap between the availability of donor livers suitable for transplantation and liver transplant demand of a growing waiting list. To expand the pool of liver grafts, donation after circulatory death is increasingly being used. Livers procured after circulatory death are exposed to a harmful period of warm Ischemia (WI) during the donation process, reducing post-transplant results significantly. Additionally, the conventional technique of static cold storage does not protect grafts that suffered WI. New dynamic preservation strategies by means of Normothermic Machine Perfusion (NMP) showed enhanced preservation of these type of grafts, but it is unknown how NMP influences liver cell biology during perfusion. Hepatocytes and cholnagiocytes have been shown to release Extracellular Vesicles (EVs) in the systemic circulation and bile, respectively. We hypothesized that EVs are released during liver NMP as well, in perfusate and bile. EVs have been separated from perfusate and bile during NMP of porcine livers, and the RNA cargo of the EVs has been sequenced to gain insights on liver cell biology during machine perfusion. Pigs were randomly allocated to undergo liver procurement either immediately after the start of surgery (no-WI, n=5) or after a period of WI of 60-minutes (clamping of thoracic aorta; WI-60, n=5). All livers (n=10) were cooled down and flushed out with ice-cold preservation solution, according to standard clinical practice. Porcine blood was collected and washed with a cell saver to obtain packed red blood cells for NMP. The hepatic artery, portal vein, and inferior vena cava were cannulated and after a period of about 2-hours of cold storage, NMP was started. All liver underwent NMP for 6-hours. Packed red blood-based perfusate samples were taken at 1, 3, and 6h of NMP; whereas, the bile produced the first 3-hours and the last 3-hours was pooled in 2 samples. Perfusate and bile samples were processed immediately for EVs separation with charge-based precipitation in a mixture of protamine and polyethylene glycol. The total RNA was extracted from EVs. Libraries of mRNA and of small RNA were prepared and analyzed for quality and size range, and sequenced on an Illumina HiSeq4000 instrument. Count-based differential expression analysis was done with R-based Bioconductor package DESeq2, and the following comparisons were performed: - Unpaired (between groups) comparison - perfusate samples WI-60 vs. no-WI - bile samples WI-60 vs. no-WI - Paired (withing group) comparison - no-WI - perfusate sample 1h vs. perfusate sample 3h - perfusate sample 1-3h vs. perfusate sample 6h - bile sample 1-3h vs. bile sample 3-6h - perfusate samples vs. bile samples - WI-60 - bile sample 1-3h vs. bile sample 3-6h - perfusate samples vs. bile samples Results were adjusted for multiple testing with the Benjamini-Hochberg procedure, to control for false discovery rate. Additionally, the function of the transcripts identified in the EVs of both groups and of the differentially expressed transcripts was investigated with gene ontology enrichment analysis for the domains \\"biological process\\" and \\"pathways\\".

Dataset Information

DCM_Titin_human_v1

Publications

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

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