# Regulation of Erythroid Cell Progenitors by the Nuclear Receptor Transcription Factor VDR

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $615,636

## Abstract

ABSTRACT: The pathways that regulate the formation and differentiation of erythroid progenitors to red blood
cells are incompletely understood. We found that the vitamin D receptor (Vdr) nuclear hormone transcription
factor gene is expressed in fetal and adult stages but not at the embryonic stage of development and is
downregulated during maturation. VDR activation by its ligand vitamin D3 results in conformational changes
that stabilize the protein and induce its translocation into the nucleus, where it recruits coregulatory complexes.
The VDR signaling pathway has been studied mostly in bone but has been largely unexplored in
erythropoiesis: published studies were performed almost entirely in leukemic cell lines (not normal primary
cells). Activation of Vdr signaling by the vitamin D3 agonist calcitriol increased the outgrowth of EryD colonies
from fetal liver and adult bone marrow, maintained progenitor potential, and delayed erythroid maturation. The
stimulation in growth of erythroid progenitors resulted in a large increase in the numbers of mature red blood
cells. The early (CD71lo/neg) but not the late (CD71hi) EryD progenitor subset of Linneg cKit+ cells was responsive
to calcitriol, independently of its calcemic effects. Activation of VDR could partially substitute for and
synergize with the stress glucocorticoid dexamethasone in enhancing progenitor proliferation compared to
either ligand alone, suggesting a role in stress erythropoiesis. This possibility is supported by our finding that
an erythroid specific deletion in Vdr that interferes with DNA binding results in a reticulocytosis that occurs
earlier and is more pronounced than in control animals in response to stress. RNA inhibition of Vdr expression
abrogated the stimulation of early erythroid progenitor growth by calcitriol. These findings suggest that Vdr has
a cell-intrinsic function in early erythroid progenitors. Activation of Vdr by calcitriol blocked the upregulation of
erythroid transcription factor genes Gata1, Fog1 and Klf1. Intriguingly, circadian rhythm genes are
upregulated by activation of Vdr and the glucocorticoid receptor Gr and oscillations in expression of the clock
gene Per1 are promoted in erythroid progenitors. The clock gene Bmal1 is required for the proliferative
response to dexamethasone. Therefore, the overarching hypothesis of this proposal is that Vdr and Gr
regulate erythroid progenitors in part by modulating clock gene expression and have partially redundant
functions. This application will use animal and cell culture models to explore the modulation of circadian clock
gene expression by Gr and Vdr in erythroid progenitors and functional relationships between these two nuclear
hormone receptor TFs. These studies may lead to the identification of novel molecular targets in erythroid
progenitors that can be exploited to develop new therapies for anemias and other red cell disorders. The ability
to modulate ex vivo expansion or differentiation of RBC p...

## Key facts

- **NIH application ID:** 9976495
- **Project number:** 5R01DK102945-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Margaret H Baron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,636
- **Award type:** 5
- **Project period:** 2015-04-06 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976495

## Citation

> US National Institutes of Health, RePORTER application 9976495, Regulation of Erythroid Cell Progenitors by the Nuclear Receptor Transcription Factor VDR (5R01DK102945-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976495. Licensed CC0.

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