The genetic mechanisms underlying the continued expression of the gamma-globin genes during the adult stage in deletional hereditary persistence of fetal hemoglobin (HPFH) and deltabeta-thalassemias are not completely understood. Herein, we investigated the possible involvement of transcription factors, using the suppression subtractive hybridization (SSH) method as an initial screen to identify differentially expressed transcripts in reticulocytes from a normal and a HPFH-2 subject. Some of the detectable transcripts may participate in globin gene regulation. Quantitative real-time PCR (qRT-PCR) experiments confirmed the downregulation of ZHX2, a transcriptional repressor, in two HPFH-2 subjects and in a carrier of the Sicilian deltabeta-thalassemia trait. The chromatin remodeling factors ARID1B and TSPYL1 had a very similar pattern of expression with an incremental increase in HPFH and decreased expression in deltabeta-thalassemia. These differences suggest a mechanism to explain the heterocellular and pancellular distribution of fetal hemoglobin in deltabeta-thalassemia and deletional HPFH, respectively. Interestingly, alpha-globin mRNA levels were decreased, similar to beta-globin in all reticulocyte samples analyzed.