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Series GSE134267 Query DataSets for GSE134267
Status Public on Mar 03, 2020
Title Dnmt3a and Dnmt3b-mediated decommissioning of fetal enhancers linked to kidney disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation.
We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2Cre Dnmt3a/3b) and kidney tubule cells (KspCre Dnmt3a/3b). We characterized KspCre Dnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells.
KspCre Dnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid–induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion.
Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.
Overall design WGBS of Cdh16 positive cell from kidneys of 3 weeks old control mice and KspCreDnmt3a/3b double knock-out mice (week 3); RRBS of kidneys from 3 weeks old control mice, Six2CreDnmt3a/3b double knock-out mice, and KspCreDnmt3a/3b double knock-out mice (week 3); RNA-seq of kidneys from 3 weeks old control mice and KspCreDnmt3a/3b double knock-out mice.
Web link
Contributor(s) Guan Y, Liu H, Susztak K
Citation(s) 32127410
Submission date Jul 15, 2019
Last update date Mar 08, 2020
Contact name Hongbo Liu
Organization name University of Pennsylvania
Street address 3400 Civic Center Blvd
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL21273 HiSeq X Ten (Mus musculus)
Samples (19)
GSM3940763 WGBS-Control-3W-Cdh16Pos
GSM3940764 WGBS-KspCreDKO-3W-Cdh16Pos
GSM3940765 RRBS-Control-3W-WK-1
BioProject PRJNA554599
SRA SRP214596

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Supplementary file Size Download File type/resource
GSE134267_RAW.tar 824.6 Mb (http)(custom) TAR (of COV, TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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