Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Functional methylome analysis of human diabetic kidney disease
Jihwan Park, … , Matthew Palmer, Katalin Susztak
Jihwan Park, … , Matthew Palmer, Katalin Susztak
Published June 6, 2019
Citation Information: JCI Insight. 2019;4(11):e128886. https://doi.org/10.1172/jci.insight.128886.
View: Text | PDF
Research Article Genetics

Functional methylome analysis of human diabetic kidney disease

  • Text
  • PDF
Abstract

In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1–based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.

Authors

Jihwan Park, Yuting Guan, Xin Sheng, Caroline Gluck, Matthew J. Seasock, A. Ari Hakimi, Chengxiang Qiu, James Pullman, Amit Verma, Hongzhe Li, Matthew Palmer, Katalin Susztak

×

Figure 3

Differential methylation is driven by cell composition and cell type–specific changes.

Options: View larger image (or click on image) Download as PowerPoint
Differential methylation is driven by cell composition and cell type–spe...
(A) WGBS DNA methylation level (control and DKD) followed by DMR highlight, human kidney H3K27ac ChIP-seq, ChromHMM data, and RNA expression (by RNA sequencing). (B) The expression of Slc26a1 and Itgb2 in mouse kidney cells as identified by single-cell RNA sequencing. (C) Normalized enrichment of DMR by tissue-specific promoter regions. The y axis is the number of tissue-specific active promoters overlapping with hyper- and hypo-DMRs normalized by total length of tissue-specific active promoters. (D) Periodic acid–Schiff staining of kidney sections from control and DKD samples. (E) In silico deconvolution (by CIBERSORT) of bulk RNA sequencing data from normal and DKD human samples. Colors represent relative immune cell fractions in different samples.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts