Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles.
Hum Mol Genet
; 29(21): 3465-3476, 2021 01 06.
Article
en En
| MEDLINE
| ID: mdl-33001180
ABSTRACT
Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q < 0.05) differentially methylated regions (DMRs) that distinguished DS from typical development and idiopathic developmental delay were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons with previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q < 0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q < 0.05) enriched for blood-specific chromatin states. A ~28 kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q < 0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early life mechanisms of epigenomic dysregulation resulting from trisomy 21.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sulfitos
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Genoma Humano
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Síndrome de Down
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Metilación de ADN
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Epigénesis Genética
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Subunidad alfa 2 del Factor de Unión al Sitio Principal
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Pruebas con Sangre Seca
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
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Humans
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Male
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Newborn
Idioma:
En
Revista:
Hum Mol Genet
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos