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1. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author

Petersen, R, Lambourne, JJ, Javierre, BM, Grassi, L, Kreuzhuber, R, Ruklisa, D, Rosa, IM, Tomé, AR, Elding, H, Van Geffen, JP, Jiang, T, Farrow, S, Cairns, J, Al-Subaie, AM, Ashford, S, Attwood, A, Batista, J, Bouman, H, Burden, F, Choudry, FA, Clarke, L, Flicek, P, Garner, SF, Haimel, M, Kempster, C, Ladopoulos, V, Lenaerts, A-S, Materek, PM, McKinney, H, Meacham, S, Mead, D, Nagy, M, Penkett, CJ, Rendon, A, Seyres, D, Sun, B, Tuna, S, Van Der Weide, M-E, Wingett, SW, Martens, JH, Stegle, O, Richardson, S, Vallier, L, Roberts, DJ, Freson, K, Wernisch, L, Stunnenberg, HG, Danesh, J, Fraser, P, Soranzo, N, Butterworth, AS, Heemskerk, JW, Turro, E, Spivakov, M, Ouwehand, WH, Astle, WJ, Downes, K, Kostadima, M, and Frontini, M

Subjects
Blood Platelets, Enhancer Elements, Genetic, Erythroblasts, Genetic Variation, Humans, Promoter Regions, Genetic, Megakaryocytes, Chromatin, 3. Good health
Abstract

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.

2. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.

Author

Sampaziotis F, Justin AW, Tysoe OC, Sawiak S, Godfrey EM, Upponi SS, Gieseck RL 3rd, de Brito MC, Berntsen NL, Gómez-Vázquez MJ, Ortmann D, Yiangou L, Ross A, Bargehr J, Bertero A, Zonneveld MCF, Pedersen MT, Pawlowski M, Valestrand L, Madrigal P, Georgakopoulos N, Pirmadjid N, Skeldon GM, Casey J, Shu W, Materek PM, Snijders KE, Brown SE, Rimland CA, Simonic I, Davies SE, Jensen KB, Zilbauer M, Gelson WTH, Alexander GJ, Sinha S, Hannan NRF, Wynn TA, Karlsen TH, Melum E, Markaki AE, Saeb-Parsy K, and Vallier L

Subjects
Animals, Bile Ducts, Extrahepatic cytology, Bile Ducts, Extrahepatic injuries, Biliary Tract cytology, Biliary Tract injuries, Biliary Tract physiology, Cell Transplantation, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Epithelial Cells drug effects, Epithelial Cells metabolism, Gallbladder injuries, Humans, In Vitro Techniques, Keratin-19 metabolism, Keratin-7 metabolism, Mice, Organoids cytology, Organoids drug effects, Organoids metabolism, Secretin pharmacology, Somatostatin pharmacology, Tissue Scaffolds, gamma-Glutamyltransferase metabolism, Bile Ducts, Extrahepatic physiology, Epithelial Cells cytology, Gallbladder physiology, Organoids physiology, Regeneration physiology, Tissue Engineering methods
Abstract

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

Published
2017
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3. Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Author

Petersen R, Lambourne JJ, Javierre BM, Grassi L, Kreuzhuber R, Ruklisa D, Rosa IM, Tomé AR, Elding H, van Geffen JP, Jiang T, Farrow S, Cairns J, Al-Subaie AM, Ashford S, Attwood A, Batista J, Bouman H, Burden F, Choudry FA, Clarke L, Flicek P, Garner SF, Haimel M, Kempster C, Ladopoulos V, Lenaerts AS, Materek PM, McKinney H, Meacham S, Mead D, Nagy M, Penkett CJ, Rendon A, Seyres D, Sun B, Tuna S, van der Weide ME, Wingett SW, Martens JH, Stegle O, Richardson S, Vallier L, Roberts DJ, Freson K, Wernisch L, Stunnenberg HG, Danesh J, Fraser P, Soranzo N, Butterworth AS, Heemskerk JW, Turro E, Spivakov M, Ouwehand WH, Astle WJ, Downes K, Kostadima M, and Frontini M

Subjects
Chromatin, Humans, Promoter Regions, Genetic, Blood Platelets physiology, Enhancer Elements, Genetic, Erythroblasts chemistry, Genetic Variation, Megakaryocytes chemistry
Abstract

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.

Published
2017
Full Text
View/download PDF

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