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Nat Commun. 2019 Mar 19;10(1):1252. doi: 10.1038/s41467-019-09198-7.

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Author information

1
Department of Medical and Clinical Genetics, University of Helsinki, FI-00014, Helsinki, Finland.
2
Genome-Scale Biology, Research Programs Unit, University of Helsinki, FI-00014, Helsinki, Finland.
3
Department of Biosciences and Nutrition, Karolinska Institutet, SE 171 77, Stockholm, Sweden.
4
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77, Stockholm, Sweden.
5
Department of Clinical Genetics, Oulu University Hospital, FI-90029, Oulu, Finland.
6
PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
7
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, FI-00014, Helsinki, Finland.
8
Clinicum, University of Helsinki, FI-00014, Helsinki, Finland.
9
HUSLAB, Helsinki University Hospital, FI-00029, Helsinki, Finland.
10
Cancer and Translational Medicine Research Unit, University of Oulu, FI-90014, Oulu, Finland.
11
Department of Clinical Genetics, Helsinki University Hospital, FI-00029, Helsinki, Finland.
12
Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, 02114, MA, USA.
13
The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
14
Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, CH-4031, Switzerland.
15
Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
16
Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, FI-90014, Oulu, Finland.
17
Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
18
Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, FI-00029, Helsinki, Finland.
19
Rare Diseases Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00029, Helsinki, Finland.
20
Department of Rheumatology, Helsinki University Hospital, FI-00029, Helsinki, Finland.
21
ORTON Orthopaedic Hospital, FI-00280, Helsinki, Finland.
22
Department of Medical and Clinical Genetics, University of Helsinki, FI-00014, Helsinki, Finland. outi.kilpivaara@helsinki.fi.
23
Genome-Scale Biology, Research Programs Unit, University of Helsinki, FI-00014, Helsinki, Finland. outi.kilpivaara@helsinki.fi.
24
Department of Medical and Clinical Genetics, University of Helsinki, FI-00014, Helsinki, Finland. lauri.aaltonen@helsinki.fi.
25
Genome-Scale Biology, Research Programs Unit, University of Helsinki, FI-00014, Helsinki, Finland. lauri.aaltonen@helsinki.fi.
26
Department of Biosciences and Nutrition, Karolinska Institutet, SE 171 77, Stockholm, Sweden. lauri.aaltonen@helsinki.fi.

Abstract

Clonal 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.

PMID:
30890702
PMCID:
PMC6424975
DOI:
10.1038/s41467-019-09198-7
[Indexed for MEDLINE]
Free PMC Article

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