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.
Highlights
As a process that broadly informs stem cell biology, hematopoietic stem cells produce diverse progenitor cells that differentiate into blood cells, ensuring physiological homeostasis and the capacity to respond to stress [1,2,3]
We propose that the GATA factor-adenosine circuit integrates with other solute carrier (SLC) to establish/maintain the small molecule constitution of progenitor cells as a new mechanism to control blood cell development
Given the large number of SLC transporters not studied in hematopoiesis, we evaluated GATA1- and GATA2-regulated genes in genetic rescue and enhancer-mutant systems, respectively, to identify GATA factor-regulated SLCs
Summary
As a process that broadly informs stem cell biology, hematopoietic stem cells produce diverse progenitor cells that differentiate into blood cells, ensuring physiological homeostasis and the capacity to respond to stress [1,2,3]. Erythroid progenitor cells differentiate into precursor cells that progressively mature into enucleated reticulocytes and erythrocytes [4]. The GATA transcription factors GATA2 and GATA1 instigate genetic networks in hematopoietic stem and progenitor cells (HSPCs), erythroid precursor cells and erythroblast progeny [7]. GATA2 is expressed in erythroid precursor cells, and as GATA1 increases, it acquires the capacity to repress Gata transcription [8]. This GATA switch often decreases or increases GATA factor target gene transcription and impacts hundreds to thousands of proteins in the erythroblast proteome [9,10,11,12]. The target genes include members of large gene families, e.g. G-proteincoupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
