Abstract: FR-PO917
Dynamic Chromatin Accessibility at Poised Developmental Enhancers of Nephron Progenitors
Session Information
- Development, Stem Cells, Regenerative Medicine - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 501 Development, Stem Cells, and Regenerative Medicine: Basic
Authors
- Song, Renfang, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Baddoo, Melody C., Tulane University School of Medicine, New Orleans, Louisiana, United States
- Liu, Hongbing, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Saifudeen, Zubaida R., Tulane University School of Medicine, New Orleans, Louisiana, United States
- El-Dahr, Samir S., Tulane University School of Medicine, New Orleans, Louisiana, United States
Background
Remodeling of chromatin accessibility at dynamic lineage-specific enhancers has emerged as a key mechanism in the control of cell fate in health and disease. Recent studies defining the gene regulatory network of nephron progenitor cells (NPC) have identified cis-acting modules bound to the master transcription factors (mTF) Six2, Osr1, and Wt1. However, it is unclear how these combinatorial factors gain access to chromatin to define enhancer function. In this study, we mapped the chromatin landscape of NPC to determine accessibility of developmental enhancers to mTFs during the NPC lifespan.
Methods
Self-renewing young (E13.5, E16.5), and differentiating old (P0 and P2) Six2+/GFP+ NPCs were subjected to genome-wide ATAC-seq to map open chromatin regions, i.e., accessible enhancers. Chromatin states (poised, active, repressed) of enhancers were determined by ChIP-seq of H3K4me1, H3K27ac, and H3K27me3, respectively. Enhancer access and chromatin states were integrated with genome-wide mTF binding (ChIP-seq) and gene expression (RNA-seq).
Results
We examined 80 poised NPC genes that bind the three mTFs and show >4-fold increase in mRNA expression during NPC lifespan. mTFs occupancy corresponded to K4me1-marked (poised) chromatin regions in young NPC and to K4me1/K27ac-marked active enhancers in old NPC. Surprisingly, activation of differentiation poised enhancers (and gene transcription) correlated with progressive reduction in the size of open chromatin regions and thus to accessible cis-acting elements. In comparison, NPC lacking the H3K27 methyltransferases, Ezh1 and Ezh2, displayed persistent open chromatin at poised enhancers.
Conclusion
Progressive restriction of access to dynamic developmental enhancers may act as a gateway to fine-tune the timing of differentiation gene expression and cessation of nephrogenesis. Targeted epigenome editing of developmental enhancers may be a useful strategy to manipulate NPC fate and lifespan.
Funding
- NIDDK Support