# Epigenetic Control of Nephron Progenitor Cell Lifespan

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $353,926

## Abstract

Low nephron endowment causes hypertension, chronic kidney disease, and end-stage renal disease
requiring renal replacement therapy in children and adults. The premise of multi-potent progenitor cell-
based replacement therapy for individuals with low nephron endowment critically depends on scientific and
technical advances that foster efficient propagation of native or pluripotent cell-derived nephron progenitor
cells (NPC). Genetic and functional analyses in mice indicate that NPC residing in the cap mesenchyme
“age” during maturation, i.e., while Young E13 NPC stay in the niche and engage in self-renewal, Old P0-
P2 NPC have a shorter life span because they exit the niche at a higher rate and differentiate into nascent
nephrons. The biological basis of NPC aging is not well understood. Changes in the niche
microenvironment are not sufficient to explain Old NPC's greater propensity to differentiate since P2-NPC
cannot sustain their progenitor state even in optimal growth factor media. Our preliminary studies using
genome-wide mapping of open (accessible) chromatin identified intrinsic age-associated chromatin state
transitions in Young and Old NPC. This exciting finding prompted us to hypothesize that Old NPC are
epigenetically “primed” for differentiation, which contributes to their limited life span. Specific Aim 1 will
utilize an integrative system biology approach to delineate the active enhancer landscape and
transcriptional regulatory network of the Young and Old NPC. We will construct a comprehensive map of
the age-dependent chromatin state transitions in freshly isolated Young (E13) and Old (P0-P2) NPC, and
integrate this knowledge with enhancer histone signatures, transcriptional profiles, and transcription factor
occupancy. We will also determine whether ex vivo expansion triggers remodeling of the chromatin
landscape by comparing the epigenomic profiles of native and expanded Young and Old NPC. In Specific
Aim 2, we will test the hypothesis that the Polycomb Repressive Complex 2 (PRC2) restrains remodeling of
differentiation gene enhancers in the Young NPC. Using gene targeting and epigenome profiling, we will
demonstrate the critical role of PRC2 in controlling access to enhancers of Cdkn2a/p16 and Wnt4. We will
utilize CRISPR dCas9-targeted epigenome editing to re-write the histone signature of developmental
enhancers and rejuvenate the PRC2-mutant NPC. Successful completion of these aims has the potential
to advance the field of kidney development in general, but it will especially benefit the efforts of nephron
regeneration. Knowledge of the enhancer landscape of nephron progenitors during maturation, which does
not currently exist, can potentially open the way to development of targeted epigenetic therapy to maintain
the stemness or rejuvenate the aging NPC, and to refine existing NPC propagation protocols.

## Key facts

- **NIH application ID:** 9966977
- **Project number:** 5R01DK114050-04
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Samir S El-Dahr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,926
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966977

## Citation

> US National Institutes of Health, RePORTER application 9966977, Epigenetic Control of Nephron Progenitor Cell Lifespan (5R01DK114050-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9966977. Licensed CC0.

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