Nucleated red blood cells explain most of the association between DNA methylation and gestational age

Haftorn, Kristine L.; Denault, William Robert Paul; Lee, Yunsung; Page, Christian M.; Romanowska, Julia; Lyle, Robert; Næss, Øyvind; Kristjansson, Dana; Magnus, Per; Håberg, Siri E.; Bohlin, Jon; Jugessur, Astanand

doi:10.1038/s42003-023-04584-w

Cited by 7 publications

(8 citation statements)

References 88 publications

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“…NFI-factors were implicated in alpha-globin gene expression preference in an in vitro chicken erythrocyte system 24 . DNA methylation within the NFIX gene body was strongly associated with gestational age at birth in nucleated red blood cells derived from human cord blood 25 , 26 . In a comparison of human BM- and fetal liver-derived erythroblasts, differential DNA methylation regions were associated with NFI motifs globally and at specific CpG sites within the NFIX gene 18 .…”

Section: Discussionmentioning

confidence: 99%

Erythroid lineage chromatin accessibility maps facilitate identification and validation of NFIX as a fetal hemoglobin repressor

Chaand¹,

Fiore²,

Johnston³

et al. 2023

Commun Biol

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Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on sorted erythroid lineage cells derived from bone marrow (BM) or cord blood (CB), representing adult and fetal states, respectively. BM to CB cell ATAC-seq profile comparisons revealed genome-wide enrichment of NFI DNA binding motifs and increased NFIX promoter chromatin accessibility, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification and validation of NFIX as a new target for HbF activation has implications in the development of therapeutics for hemoglobinopathies.

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Section: Discussionmentioning

confidence: 99%

Erythroid lineage chromatin accessibility maps facilitate identification and validation of NFIX as a fetal hemoglobin repressor

Chaand¹,

Fiore²,

Johnston³

et al. 2023

Commun Biol

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“…It is located in the promoter region of the nuclear corepressor 2 gene ( NCOR2, formerly known as SMRT ). CpGs in this gene have been identified in multiple EWASs of GA as well as in several GA clocks [ 4 , 7 , 9 , 34 , 37 , 38 ]. NCOR2 encodes a nuclear receptor corepressor that facilitates transcriptional repression by recruiting histone deacetylase complexes (HDACs) and chromatin-remodeling factors [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…CpGs linked to the insulin-like growth factor 2 mRNA-binding protein 1 gene ( IGF2BP1) have also been consistently associated with GA [ 4 , 7 , 9 , 34 , 37 , 38 ]. cg18183624, located within the promoter region of IGF2BP1 , was assigned a selection probability of 0.996 in our stability selection analyses.…”

Section: Discussionmentioning

confidence: 99%

Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites

et al. 2023

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Background DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA. Results We applied a statistical approach called ‘stability selection’ to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns. Conclusion We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.

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“…Sex was additionally adjusted for in the Sex Combined analysis. Gestational age and birthweight met this cutoff in males, but not females, and were not corrected for because the effect of gestational age on DNA methylation has been found to mostly be due to nRBC proportion [ 37 ] and birthweight is largely dependent on gestational age. Sex chromosomes were included in Females Only and Males Only comparison but not the Sex Combined comparison.…”

Section: Methodsmentioning

confidence: 99%

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

Mouat,

Li,

Myint

et al. 2023

Hum Genomics

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Background Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. Methods We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. Results We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. Conclusions A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

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Nucleated red blood cells explain most of the association between DNA methylation and gestational age

Cited by 7 publications

References 88 publications

Erythroid lineage chromatin accessibility maps facilitate identification and validation of NFIX as a fetal hemoglobin repressor

Erythroid lineage chromatin accessibility maps facilitate identification and validation of NFIX as a fetal hemoglobin repressor

Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

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