Researchers have uncovered how a trace metal controls the generation of red blood cells, which are critical for life.

Scientists at the University of Wisconsin School of Medicine and Public Health demonstrated that two genes regulate the intake and expulsion of zinc from precursors to red blood cells. This process controls whether the cells survive and differentiate into red blood cells, according to Emery Bresnick, PhD, professor of cell and regenerative biology, director of the University of Wisconsin Blood Research Program, and lead author of the research.

“Zinc-deficiency anemia is a public-health problem world-wide, but we never really understood whether zinc directly or indirectly influences the generation and function of red blood cells,” he said.

Bresnick and his colleagues focused their attention on the relationship between GATA-1, a protein responsible for regulating genetic information in cells that become red blood cells, and the iron-containing compound heme, an essential component of hemoglobin protein in red blood cells.

The latter mediates the transport of oxygen to tissues in the body and is therefore essential for life.

In this relationship, heme regulates the ability of GATA-1 to control genes in red blood cell precursors.

By determining how GATA-1 and heme control genes that produce cellular messenger RNAs and corresponding proteins, Bresnick’s team identified a dynamic gene regulatory process that initially elevates intracellular zinc, allowing the red cell precursor to survive, and subsequently decreases zinc, enabling the final steps in the cellular remodeling in which the precursor cell expels its nucleus to generate a functional red blood cell.

The therapeutic implications of this discovery relate to the need to develop treatments for blood diseases called ineffective erythropoiesis disorders, which include myelodysplastic syndrome disorders and an assortment of anemias with unexplained causes. 

In these disorders, roadblocks prevent red blood cell generation, and this defective process is often resistant to the common therapeutic agent that stimulates red blood cell production, erythropoietin.

“The discovery of a new mechanism that helps precursor cells survive and controls the ‘terminal’ differentiation step constitutes a new paradigm that can be investigated further in the context of these pathologies,” Bresnick said. “From a fundamental perspective, this study illustrates a new way in which a cellular cofactor (heme) triggers a transcriptional regulator (GATA-1) to orchestrate the levels of an intracellular trace metal to control cellular differentiation.”

The findings recently appeared in the journal Developmental Cell.

The project was a multi-disciplinary collaboration including Nobuyuki Tanimura, postdoctoral fellow in the Bresnick laboratory who led the experimental effort; Joshua Coon, professor of biomolecular chemistry; Judith Burstyn, professor of chemistry; and Jian Xu, an assistant professor and genome scientist from University of Texas Southwestern Medical Center.