Defining the dynamic chromatin landscape of mouse nephron progenitors

Abstract

Six2 + cap mesenchyme cells, also called nephron progenitor cells (NPC), are precursors of all epithelial cell types of the nephron, the filtering unit of the kidney. Current evidence indicates that perinatal ‘old’ NPC have a greater tendency to exit the progenitor niche and differentiate into nascent nephrons than their embryonic ‘young’ counterpart. Understanding the underpinnings of NPC development may offer insights to rejuvenate old NPC and expand the progenitor pool. Here, we compared the chromatin landscape of young and old NPC and found common features reflecting their shared lineage but also intrinsic differences in chromatin accessibility and enhancer landscape supporting the view that old NPC are epigenetically poised for differentiation. Annotation of open chromatin regions and active enhancers uncovered the transcription factor Bach2 as a potential link between the pro-renewal MAPK/AP1 and pro-differentiation Six2/b-catenin pathways that might be of critical importance in regulation of NPC fate. Our data provide the first glimpse of the dynamic chromatin landscape of NPC and serve as a platform for future studies of the impact of genetic or environmental perturbations on the epigenome of NPC.

ATAC-seq normalization method can significantly affect differential accessibility analysis and interpretation

“…However, ATAC-seq offers many benefits over comparable assays including a lower input material requirement, shorter assay time, in situ library preparation, and further protocol adaptation to fresh-frozen tissue [11]. These advantages have permitted precise in vivo regulatory genomic assays on small populations of sorted cells [12][13][14][15][16][17].…”

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…Chromatin accessibility is a dynamic process that drives nephron development 26 . Nephron progenitors have distinct chromatin accessibility profiles that change as they differentiate 10,26 .…”

“…Chromatin accessibility is a dynamic process that drives nephron development 26 . Nephron progenitors have distinct chromatin accessibility profiles that change as they differentiate 10,26 . The role of chromatin accessibility in promotion or inhibition of kidney repair and regeneration has important implications for designing therapies for acute and chronic kidney disease 27 and may help to improve directed differentiation of kidney organoids 28 .…”

The roles of histone deacetylases in kidney development and disease

“…Therefore, the acetylation of these potential sites would be very likely associated with the nucleus localization of Six2 protein and/or transcriptional activity. Recently, our genome-wide analysis showed that Hdac1 and Six2 co-occupy the enhancer regions of NPC renewal genes and the binding of Hdac1 indicates the open chromatin at the promoter region of actively transcribed genes in NPC [ 34 ]. How HDAC1/2 to regulate Six2 function for kidney development definitely warrants further investigation.…”