Master hematopoietic transcription factors (TFs) and long noncoding RNAs (lncRNAs) coordinate shaping lineage-specific gene expression programs during hematopoietic differentiation. The architectural protein CCCTC-binding factor (CTCF) has emerged as a pivotal regulator of gene expression in cell differentiation. However, the relationship and its regulatory effect of CTCF on lncRNA genes in hematopoiesis remain elusive. We demonstrated that CTCF constrains the lncRNA DUBRtranscription throughout erythroid differentiation. DUBR is highly expressed in human hematopoietic stem and progenitor cells (HSPCs) but depleted in erythroblasts. DUBR perturbation dysregulates hematopoietic-erythroid cell differentiation genes and facilitates genome-wide activation of regulatory elements. A genomic map of RNA occupancy revealed that DUBR associates with a set of genes involved in regulating hematopoietic differentiation, including the erythroid repressor HES1, which targets a subset of regulatory elements of DUBR-dysregulated genes. Our results support the role of DUBR as a regulator of a hematopoietic differentiation gene program by coordinating the expression of genes and influencing their chromatin regulatory landscape.