RT Journal
A1 Zhou, Yichao
A1 Dogiparthi, Venkatasai Rahul
A1 Harris, Hannah L.
A1 Ray, Suhita
A1 Choudhuri, Avik
A1 Yang, Song
A1 Zhou, Yi
A1 Zon, Leonard I.
A1 Rowley, M. Jordan
A1 Hewitt, Kyle J.
T1 Regeneration alters open chromatin and cis-regulatory landscape of erythroid precursors
JF Genome Research 
JO Genome Research 
YR 2025 
FD July 01 
VO 35 
IS 7 
SP 1518 
OP 1529 
DO 10.1101/gr.279949.124 
UL http://genome.cshlp.org/content/35/7/1518.abstract 
AB Stress erythropoiesis elevates the rate of red blood cell (RBC) production as a physiological response to stressors such as anemia or hypoxia. In acute anemia, RBC progenitors and precursors temporarily rewire their transcriptome, up- and downregulating hundreds of genes to accelerate the production of mature RBCs. Effective regeneration requires communication between critical cytokine signals (e.g., BMP4) and cis-regulatory elements on chromatin which coordinate transcriptional changes. To identify cis-regulatory changes that underlie anemia-specific gene expression and cellular responses, we analyzed chromatin accessibility in populations of cells enriched for red blood cell precursors isolated from mice at a range of time points after anemia induction. Early in the anemia response, chromatin is transiently open at AP-1-containing regions, correlated with increased Jun and Fos transcript/protein levels. Jun knockdown ex vivo decreases the percentage of KIT+ erythroid precursors after anemia induction. We observe a second rewiring event at time points consistent with anemia resolution, involving repression of GATA factor-accessible regions and activation of ETS factor-accessible regions. In both mouse in vivo models and human CD34+ cells stimulated with BMP4, accessibility changes at regions with prior associations to human blood phenotypes. Dozens of BMP4- and anemia-activated loci are sensitive to natural human variation. The representation of red blood cell trait–associated loci in ATAC-seq data remains durably elevated more than 1 month after anemia resolution. Together, these findings provide a framework to understand the early establishment and late resolution of a regeneration-dependent transcriptome in RBC precursors.