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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans |
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| Author: | Kaasinen, Eevi1,2,3,4; Kuismin, Outi5,6,7; Rajamäki, Kristiina1,2,8; |
| Organizations: |
1Department of Medical and Clinical Genetics, University of Helsinki, FI-00014, Helsinki, Finland 2Genome-Scale Biology, Research Programs Unit, University of Helsinki, FI-00014, Helsinki, Finland 3Department of Biosciences and Nutrition, Karolinska Institutet, SE 171 77, Stockholm, Sweden
4Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77, Stockholm, Sweden
5Department of Clinical Genetics, Oulu University Hospital, FI-90029, Oulu, Finland 6PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland 7Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, FI-00014, Helsinki, Finland 8Clinicum, University of Helsinki, FI-00014, Helsinki, Finland 9HUSLAB, Helsinki University Hospital, FI-00029, Helsinki, Finland 10Cancer and Translational Medicine Research Unit, University of Oulu, FI-90014, Oulu, Finland 11Department of Clinical Genetics, Helsinki University Hospital, FI-00029, Helsinki, Finland 12Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, 02114, MA, USA 13The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA 14Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, CH-4031, Switzerland 15Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland 16Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, FI-90014, Oulu, Finland 17Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland 18Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, FI-00029, Helsinki, Finland 19Rare Diseases Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, FI-00029, Helsinki, Finland 20Department of Rheumatology, Helsinki University Hospital, FI-00029, Helsinki, Finland 21ORTON Orthopaedic Hospital, FI-00280, Helsinki, Finland |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 6.3 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2019092529684 |
| Language: | English |
| Published: |
Springer Nature,
2019
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| Publish Date: | 2019-09-25 |
| Description: |
AbstractClonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis. see all
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| Series: |
Nature communications |
| ISSN: | 2041-1723 |
| ISSN-E: | 2041-1723 |
| ISSN-L: | 2041-1723 |
| Volume: | 10 |
| Issue: | 1 |
| Article number: | 1252 |
| DOI: | 10.1038/s41467-019-09198-7 |
| OADOI: | https://oadoi.org/10.1038/s41467-019-09198-7 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine |
| Subjects: | |
| Funding: |
This work was supported by grants from the Academy of Finland [Finnish Centre of Excellence Programs (#250345 and #312041), and personal grants for O. Kilpivaara (#137680 and #274474) and for P.V. (#260370)], the Finnish Cancer Society, the Sigrid Juselius Foundation, Maire Lisko Foundation (personal grant for K.R.), Reumatautien tutkimussäätiö (personal grant for K.R.), Finnish Foundation for Pediatric Research & Pediatric Research Center, Helsinki University Hospital Research Funds, and the Stockmann Foundation. We acknowledge the computational resources provided by the ELIXIR node, hosted at the CSC–IT Center for Science, Finland, and funded by the Academy of Finland (#271642 and #263164), the Ministry of Education and Culture, Finland. This study makes use of data generated by the UK10K Consortium, derived from samples from ALSPAC and TwinsUK. |
| Copyright information: |
© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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https://creativecommons.org/licenses/by/4.0/ |