Network of transcription factors targeting Ikzf1 enhancers. (A) TF enrichment peaks at the Ikzf1 locus in thymocytes (T cells), CH12 (B cells), and erythoid precursors were visualized by the IGV browser. A summary of regulatory activities is provided above respective enhancer regions at the Ikzf1 locus. (B-C) A model of Ikzf1 regulation. (B) Ikzf1 enhancer-promoter interactions during hematopoiesis. Erythroid-specific factors binding at enhancer G enable interactions with the myeloid-specific promoter A and Ikaros expression during early erythropoiesis. Lympho-myeloid–specific factors binding at enhancers D and H support interactions with the lympho-myeloid–specific promoter B and Ikaros expression during lymphoid and myeloid differentiation. Lineage-specific transcription factors at these sites are depicted as color-coded circles. Arrows indicate potential interactions between cell type–specific enhancers and promoters supporting Ikzf1 expression at appropriate developmental stages. (C) Ikzf1 regulatory region activity during lymphopoiesis. The Ikzf1 lympho-myeloid promoter B, although active from the HSCs through B cell and myeloid differentiation, requires input from an enhancer to overcome the restrictive chromatin effects and PEV (yellow circle). Enhancers J, D(C), E, F, H, and I counteract PEV and raise Ikzf1 gene expression (orange circle). For Ikzf1 expression past the DN stage of T-cell development, input is required from enhancers D(C) (blue) and H (green). Induction of Ikzf1 expression in the LMPP to the level required for lymphocyte differentiation is dependent on enhancer D(C) activity (blue).