# Dynamic Regulation of Erythropoietin Gene Expression in Mammals

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2020 · —

## Abstract

Anemia, a common condition in Veteran patients, is a potent risk factor for increased
morbidity and mortality when accompanying other disease states. Current therapies for anemia
involve non-physiological bolus administration of erythropoietin (Epo), an endocrine factor produced in
the adult kidney and liver with severe anemia. Bolus Epo administration has untoward effects, including
an increased thrombotic risk and a stimulatory effect on cancer. Understanding how Epo is regulated
will allow investigators to develop rational therapies besides Epo replacement.
 Our current focus is defining molecular mechanisms regulating Epo expression in
mammals. Hypoxia Inducible Factor (HIF) transcription factors are a family of three molecular
mediators that induce a protective cellular response to hypoxia. The second HIF member, HIF-2α, is
critical for in vivo Epo gene expression. While an essential role of HIF-2α in Epo regulation is now
recognized, the factors responsible for temporal Epo gene expression in vivo, or for abnormal
repression of Epo gene expression in anemia patients, remain poorly understood.
 Although HIF-2α undergoes oxygen-dependent post-translational modifications, this
mechanism is not the sole or even major mechanism for controlling HIF-2 signaling. Activity of
HIF-1α, the founding HIF member, is controlled predominantly by oxygen-dependent post-translational
modifications of the HIF-1α protein, which result in marked changes in HIF-1α protein levels. However,
this mechanism is not the sole or even predominant mechanism for regulation of HIF-2 signaling.
Instead, HIF-2α activity is controlled by two opposing and post-translational modifications, acetylation
and deacetylation, that operate in a cyclical manner.
 Our central hypothesis is that hypoxia triggers changes in intermediary metabolism to
effect acetylation of HIF-2α. The biochemical basis for control of HIF-2α acetylation is via an entity
termed the acetate switch, which couples changes in intermediary metabolism with acetyl CoA
generation. The molecular mediator for the acetate switch is acetyl CoA synthetase 2 (Acss2), an
acetate-dependent enzyme that generates a specific pool of acetyl CoA used to induce coupled
acetylation and activation of HIF-2α. Because a subset of Acss2 transits to the nucleus during hypoxia,
the ability of Acss2 to augment HIF-2α activity may be conferred by its localization to the nuclear
compartment during stress. Deciphering precisely how Acss2 regulates HIF-2 signaling will
provide insights into normal Epo regulation, identify potential pathophysiological mechanisms
responsible for anemia, and stimulate development of novel treatments for anemia patients.

## Key facts

- **NIH application ID:** 9979759
- **Project number:** 5I01BX000446-11
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Joseph Anthony Garcia
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979759

## Citation

> US National Institutes of Health, RePORTER application 9979759, Dynamic Regulation of Erythropoietin Gene Expression in Mammals (5I01BX000446-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9979759. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*