Defining A Cohort of Anemia-Activated Cis-Elements Reveals a Mechanism Promoting Erythroid Precursor Function.

Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the Samd14 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, Samd14 is only one 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 induced 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 proliferation. Over a week-long time course of acute anemia recovery, we observed 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.