Transiently increased accessibility of anemia-sensitive cis-elements at RBC trait–associated SNPs. (A) Clustered heat map of gChromVAR Z-scores across a 35-day time course post-PHZ. (RBC) Red blood cell, (MCH) mean corpuscular height, (MCV) mean corpuscular volume, (MCHC) mean corpuscular hemoglobin concentration, (Retic) reticulocyte, (Eo) eosinophil, (HCT) hematocrit, (HGB) hemoglobin, (MPV) mean platelet volume, (WBC) white blood cell, (PLT) platelet. (B) Line graph of gChromVAR Z-scores specific to RBC traits. (C) Line graph of gChromVAR Z-scores specific to WBC traits. (D) Line graph of gChromVAR Z-scores specific to megakaryocyte traits. (E) Modeling cis-regulatory usage across the erythroid recovery timeline. At early time points in anemia recovery, erythroid precursor cells upregulate expression and activity of JUN and FOS transcription factors at AP-1 motifs on chromatin. Following activation events, erythroid expansion and differentiation includes the use of canonical E-box-GATA elements. Later in the recovery timeline—after anemia has largely resolved—GATA element use drops sharply and ETS motifs are more widely utilized. These changes are associated with transient increase in the use of cis-elements containing single nucleotide polymorphisms previously linked to RBC traits.
