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. 2022 Mar;17(3):335-355.
doi: 10.1080/15592294.2021.1900027. Epub 2021 Mar 30.

Identification of a foetal epigenetic compartment in adult human kidney

John K Wiencke  1 , Ze Zhang  2 , Devin C Koestler  3 , Lucas A Salas  4 , Annette M Molinaro  1 , Brock C Christensen  4 , Karl T Kelsey  2
Affiliations

Identification of a foetal epigenetic compartment in adult human kidney

John K Wiencke et al. Epigenetics. 2022 Mar.

Abstract

The mammalian kidney has extensive repair capacity; however, identifying adult renal stem cells has proven elusive. We applied an epigenetic marker of foetal cell origin (FCO) in diverse human tissues as a probe for developmental cell persistence, finding a 5.4-fold greater FCO proportion in kidney. Normal kidney FCO proportions averaged 49% with extensive interindividual variation. FCO proportions were significantly negatively correlated with immune-related gene expression and positively correlated with genes expressed in the renal medulla, including those involved in renal organogenesis (e.g., FGF2, PAX8, and HOXB7). FCO associated genes also mapped to medullary nephron segments in mouse and rat, suggesting evolutionary conservation of this cellular compartment. Renal cancer patients whose tumours contained non-zero FCO scores survived longer. The kidney appears unique in possessing substantial foetal epigenetic features. Further study of FCO-related gene methylation may elucidate regenerative regulatory programmes in tissues without apparent discrete stem cell compartments.

Keywords: DNA methylation; Kidney; epigenetics; foetal stem cells; stem cell niche.

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Conflict of interest statement

J.K.W. and K.T.K. are cofounders of Cellintec.

Figures

Figure 1.
Figure 1.
A-C. FCO proportions are associated with development stage, subject age and are elevated in adult kidney compared to non-renal tissues. Panel A. Schematic image of nephron (https://commons.wikimedia.org/wiki/File:Figure_41_03_03.png; permitted to use) Panel B. Horizontal box plots of median FCO proportions among adult tissues showing that adult kidney FCO proportions are higher than other solid tissues or haematopoietic cells. FCO proportions estimated in 964 normal tissue samples from 20 TCGA studies and 4 GEO studies. Panel C. Cross-sectional plot of the FCO proportions of human foetal, paediatric and adult kidney specimens and blood leukocytes by tissue donor age. Loess smoothing curves and 95% confidence intervals across different ages showing the relationship of donor age with FCO proportions. Data sources supplied in methods.
Figure 2.
Figure 2.
A-D. Gene ontology enrichment among genes associated with the FCO proportion. Panel A. The top 250 genes negatively correlated with the FCO proportion were analysed using gene ontology (GO) enrichment analysis with the PANTHER Overrepresentation Test. We present the top 20 GO biological process pathways in the table based on FDR ranking. Panel B. Top 20 GO terms enriched with genes exhibiting a positive correlation with FCO proportion based on a transcriptome-wide association analysis. Panel C. Top 20 GO terms enriched with genes exhibiting a negative correlation with FCO proportions based on restricted subset of genes containing FCO DMRs. Panel D. Top 20 GO terms enriched with genes exhibiting a positive correlation with FCO proportions based on restricted subset of genes containing FCO DMRs.
Figure 3.
Figure 3.
DNA methylation levels of FCO related genes depend on tissue type and are correlated with gene expression in adult kidney. Three examples of FCO-related DMRs in foetal kidney, adult kidney and adult blood leukocytes are shown; FGF2, PAX8, and HOXB7 genes. The upper panels show that adult leukocytes, which have a non-detectable FCO score, demonstrate higher beta values (Y-axis) compared to foetal kidney and that adult kidney methylation tracks with foetal tissues (boxed are the FCO related CpGs). Error bars represent standard deviations for 22 foetal kidneys (GSE69502 and GSE76641), 205 normal adult kidneys (TCGA), and 23 adult blood leukocytes. The lower panels depict the correlations of each CpG site methylation value with the corresponding sample FCO proportion (middle panel) and the corresponding RNA-Seq expression score (lower panel) in adult kidney.
Figure 4.
Figure 4.
A-B. Gene expression signatures positively correlated with FCO proportions localize to renal medulla in adult human kidney. Panel A. The expression of genes positively correlated with the FCO proportion are highly correlated with differentially expressed genes of the renal medulla. Metagene signature scores for FCO positively correlated genes are plotted against four published metagene expression scores of cortical and medullar biopsy depth biopsies [56] (95% confidence interval indicated by grey shades). Panel B. Heatmap showing correspondence of FCO positive and negatively correlated gene metagenes with the co-expression modules of Lindgren DA 2017[56]. Co-expression modules correspond to published quality threshold (QT) module designation and are presented in the anatomic order as presented therein.
Figure 5.
Figure 5.
Corroboration of human FCO-related gene expression using orthologous renal genes in mouse (a) and rat (b). Panel A. The expression of human orthologs of mouse kidney cell gene signatures for ascending limb of the loop of Henle cells, and the collecting duct’s principal cells are strongly correlated with FCO related gene expression. Expression of human orthologs of mouse proximal and distal convoluted cells are inversely correlated with FCO related gene expression (95% confidence interval indicated by grey shades). Panel B, left. t-SNE clustering using rat orthologs of human FCO related genes that discriminates six kidney regions in the rat. Human genes were chosen whose expression exhibited a Spearman correlation with FCO proportions of at least > |0.6|. Panel B, right. Hierarchical clustering using the top 30 influential genes in the t-SNE clusters showing association of medullary segments with genes positively correlated with FCO proportions whereas cortical nephron segments and glomerulus are influenced by gene expression negatively associated with FCO proportions.
Figure 6.
Figure 6.
Non-detectable FCO proportions within tumour tissue predict longer survival times in human clear cell renal cancer. Survival analysis was conducted using the data from TCGA. We applied a recursive partitioning algorithm, partDSA, in an effort to create homogeneous survival risk groups [88]. Panel A. partDSA survival tree for human renal clear cell carcinoma patients on TCGA. The models incorporated relevant patient variables, including patient age, gender, TMN class, tumour laterality, tumour FCO score. Panel B. Kaplan-Meier survival curves for the part DSA-identified subgroups. Panel C. Relevant survival statistics for the part DSA-identified subgroups. Panel D. Association of nondetectable FCO (FCO = 0) proportions with higher stage clear cell renal cancer tumours.
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