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

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Kaasinen , E , Kuismin , O , Rajamäki , K , Ristolainen , H , Aavikko , M , Kondelin , J , Saarinen , S , Berta , D G , Katainen , R , Hirvonen , E A M , Karhu , A , Taira , A , Tanskanen , T , Alkodsi , A , Taipale , M , Morgunova , E , Franssila , K , Lehtonen , R , Mäkinen , M , Aittomäki , K , Palotie , A , Kurki , M , Pietiläinen , O , Hilpert , M , Saarentaus , E , Niinimäki , J , Junttila , J , Kaikkonen , K , Vahteristo , P , Skoda , R C , Seppänen , M R J , Eklund , K K , Taipale , J , Kilpivaara , O & Aaltonen , L A 2019 , ' Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans ' , Nature Communications , vol. 10 , 1252 . https://doi.org/10.1038/s41467-019-09198-7

Title: Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Author: Kaasinen, Eevi; Kuismin, Outi; Rajamäki, Kristiina; Ristolainen, Heikki; Aavikko, Mervi; Kondelin, Johanna; Saarinen, Silva; Berta, Davide G.; Katainen, Riku; Hirvonen, Elina A. M.; Karhu, Auli; Taira, Aurora; Tanskanen, Tomas; Alkodsi, Amjad; Taipale, Minna; Morgunova, Ekaterina; Franssila, Kaarle; Lehtonen, Rainer; Mäkinen, Markus; Aittomäki, Kristiina; Palotie, Aarno; Kurki, Mitja; Pietiläinen, Olli; Hilpert, Morgane; Saarentaus, Elmo; Niinimäki, Jaakko; Junttila, Juhani; Kaikkonen, Kari; Vahteristo, Pia; Skoda, Radek C.; Seppänen, Mikko R. J.; Eklund, Kari K.; Taipale, Jussi; Kilpivaara, Outi; Aaltonen, Lauri A.
Contributor: University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Lauri Antti Aaltonen / Principal Investigator
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Department of Pathology
University of Helsinki, Research Program in Systems Oncology
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Children's Hospital
University of Helsinki, Department of Medicine
University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Lauri Antti Aaltonen / Principal Investigator
Date: 2019-03-19
Language: eng
Number of pages: 17
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/300685
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.
Subject: AMINO-ACID SUBSTITUTIONS
J-CHAIN GENE
CLONAL HEMATOPOIESIS
DNA METHYLATION
READ ALIGNMENT
STEM-CELLS
WEB SERVER
T-BET
MUTATIONS
MEMORY
3111 Biomedicine
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