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Kidney Week

Abstract: TH-PO767

DNA Methylation Program in Human Kidney Development

Session Information

  • Pediatric CKD
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ma, Ziyuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Li, Szu-yuan, University of Pennsylvania, Philadelphia, United States
  • Goetzl, Laura, Temple University, Philadelphia, Pennsylvania, United States
  • Pinney, Sara E., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Simmons, Rebecca, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Epidemiologic studies indicate that in utero nutritional alterations increase the risk of hypertension, and kidney disease in adults. Changes in the epigenome have been proposed to mediate the metabolic programming effect, as epigenome editing enzymes are regulated by substrates of the intermediate metabolism and changes in the epigenome can be maintained after cell division. DNA methylation is one of the most studied epigenetic factor that plays a key role in gene expression regulation and cell type specification. The methylation dynamics of human kidney development (pre and post-natal) remains unknown, therefore we analyzed genome-wide methylation changes of human kidney development and maturation.

Methods

Here we performed base resolution methylome analysis by whole genome bisulfite sequencing of human fetal kidneys, from 11.4 to 19.0 weeks of gestation and postnatal kidney tubules from 27 to 61 years of age (n=12). The SMART genome segmentation method was used to identify differentially methylated regions (DMRs). RNA-sequencing was performed to detect gene expression changes.

Results

Whole genome methylation analysis identified dynamic methylation changes during kidney development and maturation including, 5,280 regions gaining methylation (hyper-DMRs) and 4,316 regions losing methylation (hypo-DMRs) in adult kidney tubules. Methylation changes were enriched on gene regulatory regions. Hyper-DMR regions lost histone enhancer marks (H3K4me1 and H3K27ac) while hypo-DMRs gained enhancer marks. Function enrichment analysis indicated that developmental genes are gaining methylation while proximal tubule specific genes undergo demethylation. Consistently hyper-DMRs were enriched for kidney developmental transcription factors binding sites such as HOXC9 and SIX2, while hypo-DMRs were enriched for the proximal tubule-specific transcription factors (HNF family). Methylation showed correlation with gene expression such as the increase in expression of proximal tubule specific genes in adult and loss of expression of fetal genes in adult. Methylation and gene expression dynamics were conserved in mice.

Conclusion

Cytosine methylation, specifically enhancer regions, show dynamic changes in fetal development and postnatal maturation, the most prominent of them is the decrease in enhancer methylation and increase of expression of proximal tubule genes.