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| Status |
Public on Dec 04, 2020 |
| Title |
The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background: Down syndrome (DS) is associated with a wide range of phenotypes. To address the hypothesis that the genome-wide perturbation of gene regulation in DS is modulated by epigenetic changes, we performed an epigenome-wide association study (EWAS) on neonatal bloodspots comparing 196 newborns with DS and 439 newborns without DS.
Results: We identified 652 epigenome-wide significant CpGs (P<7.67x10-8) and 1,052 differentially methylated regions (DMRs) across the genome. Differential methylation at promoters/enhancers correlated with gene expression changes in DS versus non-DS fetal liver hematopoietic stem/progenitor cells (HSPC) (P<0.0001). Two of the top 3 DS-associated CpGs overlapped RUNX1, and were highly significantly hypermethylated in DS newborns (P<1.0x10-21). The top two DMRs overlapped promoters of RUNX1 and FLI1, both important regulators of megakaryopoiesis. FLI1 expression was markedly reduced in DS fetal liver HSCs (P<0.0001) and myeloid progenitors (P<0.0001). By contrast, RUNX1 expression was increased in DS fetal liver myeloid progenitors (P<0.0001), consistent with selective hypermethylation of the RUNX1 P2 promoter, which dominates in embryonic development, but sparing the P1 promoter that drives definitive hematopoiesis. Targeted sequencing of GATA1 revealed somatic, preleukemic mutations in 16.3% DS newborns, consistent with the high frequency of these mutations in DS newborns. Removal of DS newborns with GATA1 mutations had minimal impact on the EWAS results.
Conclusions: DS 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 DS. Blood-detectable DS-related epigenetic changes may underlie an array of DS outcomes, including neurologic and immune-related morbidities.
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| Overall design |
RNA-seq
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| Contributor(s) |
Muskens IS, Li S, Jackson T, Elliot N, Hansen HM, Myint SS, Pandey P, Schraw J, Roy R, Anguiano J, Goudevenou K, Siegmund KD, Lupo P, de Bruijn MF, Walsh KM, Vyas P, Ma X, Roy A, Roberts I, Wiemels JL, de Smith AJ |
| Citation(s) |
33547282 |
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| Submission date |
Nov 02, 2020 |
| Last update date |
Feb 16, 2021 |
| Contact name |
Thomas Jackson |
| E-mail(s) |
[email protected]
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| Phone |
07708811876
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| Organization name |
University of Oxford
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| Department |
paediatrics
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| Lab |
Roy
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| Street address |
weatherall institute of molecular medicine
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| City |
oxford |
| ZIP/Postal code |
ox3 nds |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA673834 |
| SRA |
SRP290809 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE160637_DS_34pos_counts.txt.gz |
4.8 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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