scholarly journals Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets

Endocrinology ◽  
2021 ◽  
Author(s):  
Yu-Chin Lien ◽  
Sara E Pinney ◽  
Xueqing Maggie Lu ◽  
Rebecca A Simmons
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Regulatory Regions ◽  
Binding Motifs ◽  
Intrauterine Growth ◽  
Gene Dysregulation ◽  
Transcription Factor Binding Motifs ◽  
Significant Expression

Abstract Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes in adulthood and the permanent alterations in gene expression implicate an epigenetic mechanism. Using a rat model of IUGR, we performed TrueSeq-HELP Tagging to assess the association of DNA methylation changes and gene dysregulation in islets. We identified 511 differentially methylated regions (DMRs) and 4377 significantly altered single CpG sites. Integrating the methylome and our published transcriptome datasets resulted in the identification of pathways critical for islet function. The identified DMRs were enriched with transcription factor binding motifs, such as Elk1, Etv1, Foxa1, Foxa2, Pax7, Stat3, Hnf1, and AR. In silico analysis of 3D chromosomal interactions using human pancreas and islet Hi-C datasets identified interactions between 14 highly conserved DMRs and 35 genes with significant expression changes at an early age, many of which persisted in adult islets. In adult islets, there were far more interactions between DMRs and genes with significant expression changes identified with Hi-C and most of them were critical to islet metabolism and insulin secretion. The methylome was integrated with our published genome-wide histone modification datasets from IUGR islets resulting in further characterization of important regulatory regions of the genome altered by IUGR containing both significant changes in DNA methylation and specific histone marks. In summary we identified novel regulatory regions in islets after exposure to IUGR suggesting that epigenetic changes at key transcription factor binding motifs and other gene regulatory regions may contribute to gene dysregulation and an abnormal islet phenotype in IUGR rats.

Hepatic IGF1 DNA methylation is influenced by gender but not by intrauterine growth restriction in the young lamb

2015 ◽  
Vol 6 (6) ◽  
pp. 558-572 ◽  
Author(s):  
D. J. Carr ◽  
J. S. Milne ◽  
R. P. Aitken ◽  
C. L. Adam ◽  
J. M. Wallace
Keyword(s):  
Dna Methylation ◽  
Growth Hormone ◽  
Sexual Dimorphism ◽  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Messenger Rna ◽  
Methylation Status ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Increased Risk

Intrauterine growth restriction (IUGR) and postnatal catch-up growth confer an increased risk of adult-onset disease. Overnourishment of adolescent ewes generates IUGR in ∼50% of lambs, which subsequently exhibit increased fractional growth rates. We investigated putative epigenetic changes underlying this early postnatal phenotype by quantifying gene-specific methylation at cytosine:guanine (CpG) dinucleotides. Hepatic DNA/RNA was extracted from IUGR [eight male (M)/nine female (F)] and normal birth weight (12 M/9 F) lambs. Polymerase chain reaction was performed using primers targeting CpG islands in 10 genes: insulin, growth hormone, insulin-like growth factor (IGF)1, IGF2, H19, insulin receptor, growth hormone receptor, IGF receptors 1 and 2, and the glucocorticoid receptor. Using pyrosequencing, methylation status was determined by quantifying cytosine:thymine ratios at 57 CpG sites. Messenger RNA (mRNA) expression of IGF system genes and plasma IGF1/insulin were determined. DNA methylation was independent of IUGR status but sexual dimorphism in IGF1 methylation was evident (M<F, P=0.008). IGF1 mRNA:18S and plasma IGF1 were M>F (both P<0.001). IGF1 mRNA expression correlated negatively with IGF1 methylation (r=−0.507, P=0.002) and positively with plasma IGF1 (r=0.884, P<0.001). Carcass and empty body weights were greater in males (P=0.002–0.014) and this gender difference in early body conformation was mirrored by sexual dimorphism in hepatic IGF1 DNA methylation, mRNA expression and plasma IGF1 concentrations.

scholarly journals Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1435
Author(s):  
Yu-Chin Lien ◽  
Paul Zhiping Wang ◽  
Xueqing Maggie Lu ◽  
Rebecca A. Simmons
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Transcription Factor Binding ◽  
Binding Motifs ◽  
Factor Binding ◽  
Intrauterine Growth ◽  
Gene Dysregulation ◽  
Genome Wide

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

scholarly journals The value of DNA methylation profiling in characterizing preeclampsia and intrauterine growth restriction

2017 ◽  
Author(s):  
Samantha L Wilson ◽  
Katherine Leavey ◽  
Brian Cox ◽  
Wendy P Robinson
Keyword(s):  
Dna Methylation ◽  
Intrauterine Growth Restriction ◽  
Late Onset ◽  
Growth Restriction ◽  
Hypertensive Disorder ◽  
Intrauterine Growth ◽  
Healthy Pregnancy ◽  
Genome Wide ◽  
Illumina Humanmethylation450 ◽  
Clinical Diagnoses

AbstractPlacental health is a key component to healthy pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analyzed these separately. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use them to better understand the relationships between these related disorders.Placental samples from a discovery cohort (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To minimize gestational age (GA) effects, EOPE samples were compared to pre-term controls (GA <37 weeks), while LOPE and IUGR were compared to term controls (GA >37 weeks). There were 1703 differentially methylated (DM) sites (FDR<0.05, Δβ>0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 EOPE sites, 599 were validated in the second cohort. These sites cluster samples from both cohorts into 3 distinct methylation clusters. Interestingly, LOPE samples diagnosed between 34-36 weeks with co-occurring IUGR clustered with the EOPE methylation cluster. DNAm profiling may provide an independent tool to refine clinical diagnoses into subgroups with more uniform pathology. The challenges in reproducing genome-wide DNAm studies are also discussed.

scholarly journals Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

2017 ◽  
Author(s):  
Annie Vogel Ciernia ◽  
Milo Careaga ◽  
Janine LaSalle ◽  
Paul Ashwood
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Allergic Asthma ◽  
Transcription Factor Binding ◽  
Autism Spectrum ◽  
Differentially Expressed ◽  
Differentially Methylated Regions ◽  
Binding Motifs ◽  
Factor Binding ◽  
Transcription Factor Binding Motifs

AbstractDysregulation in immune responses during pregnancy increase the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain’s resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions (DMRs) were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed associated genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.Main Points:Maternal allergic asthma induces changes in DNA methylation and transcription in juvenile offspring microgliaDifferentially methylated regions are enriched for functions and transcription factor binding motifs involved in inflammation and microglial developmentDifferentially expressed genes and differentially methylated regions are enriched for genes dysregulated in Autism Spectrum Disorders

scholarly journals MethMotif: an integrative cell specific database of transcription factor binding motifs coupled with DNA methylation profiles

2018 ◽  
Vol 47 (D1) ◽  
pp. D145-D154 ◽  
Author(s):  
Quy Xiao Xuan Lin ◽  
Stephanie Sian ◽  
Omer An ◽  
Denis Thieffry ◽  
Sudhakar Jha ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Transcription Factor Binding ◽  
Binding Motifs ◽  
Factor Binding ◽  
Transcription Factor Binding Motifs
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