Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

Abstract

Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor selfrenewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNAseq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count.

High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy

“…Regarding the analysis of the determinants of podocyte differentiation, our study has relevance as podo‐ cyte dedifferentiation may occur in the context of podocyte injuries (17,18). Moreover, previous analyses of the alteration of mitochondrial bioenergetics were performed in diabetic podocytes that were obtained from rats and mice, which could differ from human podocytes (31, 32) or between different mouse strains (33). Moreover, the situation is unclear in mice podocytes, as Wang et al .…”

“…injuries (17,18). Moreover, previous analyses of the alteration of mitochondrial bioenergetics were performed in diabetic podocytes that were obtained from rats and mice, which could differ from human podocytes (31,32) or between different mouse strains (33). Moreover, the situation is unclear in mice podocytes, as Wang et al (34) reported an alteration of oxphos by hyperglycemia, whereas other authors showed the opposite (10,35).…”

Development of the Mammalian Kidney

“…Efforts are already underway in a human GUDMAP initiative (www.gudmap.org). Early studies have revealed some striking differences in Six1 and Six2 regulation within the nephron progenitor compartment (O’Brien et al, 2015). Given the critical role of Six-factors in maintaining nephron progenitors, these results may have relevance to differences in the duration of nephrogenesis and the final nephron count which differ dramatically between mouse and human kidney…”

Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening

“…Marker lists were exported and compared with published human single cell data 29,30 , and established gene expression profiles from mouse 31 . Gene ontology analysis was performed using TopFunn 32 .…”