GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism.

Abstract

Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

• Authors: Nicole M Zwifelhofer, Xiaoli Cai, Ruiqi Liao, Bin Mao, Daniel J Conn, Charu Mehta, Sunduz Keles, Yang Xia, Emery H Bresnick
• Journal: PLoS genetics (PLoS Genet) Vol. 16 Issue 12 Pg. e1009286 (12 2020) ISSN: 1553-7404 [Electronic] United States
• PMID: 33370779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Equilibrative Nucleoside Transporter 1
• GATA Transcription Factors
• SLC29A1 protein, mouse
• Adenosine

Topics

• Adenosine (metabolism)
• Animals
• Cells, Cultured
• Equilibrative Nucleoside Transporter 1 (genetics, metabolism)
• Erythropoiesis
• GATA Transcription Factors (metabolism)
• Mice
• Mice, Inbred C57BL