TY  - JOUR
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
Y1  - 2025/07/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1518 
EP  - 1529 
DO  - 10.1101/gr.279949.124 
VL  - 35 
IS  - 7 
UR  - http://genome.cshlp.org/content/35/7/1518.abstract 
N2  - 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. 
ER  -