Defining a cohort of anemia-activated cis elements reveals a mechanism promoting erythroid precursor function

• Published in: Blood advances 2023-10, Vol.7 (20), p.6325-6338
• Main Authors: Zhou, Yichao, Dogiparthi, Venkatasai Rahul, Ray, Suhita, Schaefer, Meg A., Harris, Hannah L., Rowley, M. Jordan, Hewitt, Kyle J.
• Format: Article
• Language: English
• Subjects: Red Cells, Iron, and Erythropoiesis
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022009163

•Genes associated with E-box-GATA enhancers are upregulated at specific time points during acute anemia recovery within erythroid precursors.•Anemia-activated Ssx2ip promotes erythroid progenitor and precursor cell cycle progression and proliferation. [Display omitted] Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the sterile alpha motif domain-14 enhancer locus (S14E), defined by a CANNTG-spacer-AGATAA composite motif and occupied by GATA1 and TAL1 transcription factors, is required for survival in severe anemia. However, S14E is only 1 of dozens of anemia-activated genes containing similar motifs. In a mouse model of acute anemia, we identified populations of expanding erythroid precursors, which increased expression of genes that contain S14E-like cis elements. We reveal that several S14E-like cis elements provide important transcriptional control of newly identified anemia-inducing genes, including the Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor/precursor cell activities, cell cycle regulation, and cell proliferation. Over a weeklong course of acute anemia recovery, we observed that erythroid gene activation mediated by S14E-like cis elements occurs during a phase coincident with low hematocrit and high progenitor activities, with distinct transcriptional programs activated at earlier and later time points. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery, and phenotypic variability within human populations.