The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Feb 4, 2021

Contributor: Ivo S Muskens,Shaobo Li,Thomas Jackson,Natalina Elliot,Helen M Hansen,Swe Swe Myint,Priyatama Pandey,Jeremy M Schraw,Ritu Roy,Joaquin Anguiano,Katerina Goudevenou,Kimberly D Siegmund,Philip J Lupo,Marella F T R de Bruijn,Kyle M Walsh,Paresh Vyas,Xiaomei Ma,Anindita Roy,Irene Roberts,Joseph L Wiemels,Adam J de Smith

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

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About The Expert

Ivo S Muskens

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.

Shaobo Li

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.

Thomas Jackson

Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.

Natalina Elliot

Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.

Helen M Hansen

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

Swe Swe Myint

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.

Priyatama Pandey

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.

Jeremy M Schraw

Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.

Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, TX, USA.

Ritu Roy

Computational Biology and Informatics, University of California San Francisco, San Francisco, CA, USA.

Joaquin Anguiano

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

Katerina Goudevenou

Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.

Kimberly D Siegmund

Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Philip J Lupo

Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.

Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, TX, USA.

Marella F T R de Bruijn

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Kyle M Walsh

Department of Neurosurgery, Duke University, Durham, NC, USA.

Department of Pediatrics, Duke University, Durham, NC, USA.

Paresh Vyas

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Xiaomei Ma

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

Anindita Roy

Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.

Irene Roberts

Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK.

Joseph L Wiemels

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.

Adam J de Smith

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. adam.desmith@med.usc.edu.

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. adam.desmith@med.usc.edu.

References

PubMed