Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain beta-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of gamma-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by beta-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or gamma-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin). Current research has focused on elucidating the pathways involved in the maintenance/reactivation of gamma-globin in adult life. To better understand these pathways, we generated new beta-globin locus yeast artificial chromosome transgenic mice bearing the (A)gamma-globin -175 T>C or -195 C>G hereditary persistence of fetal hemoglobin mutations to model naturally occurring hereditary persistence of fetal hemoglobin. Adult -175 and -195 mutant b-YAC mice displayed a hereditary persistence of fetal hemoglobin phenotype, as measured at the mRNA and protein levels. The molecular basis for these phenotypes was examined by chromatin immunoprecipitation of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2, and LDB1. In -175 HPFH versus wild-type samples, the occupancy of LMO2, TAL1 and LDB1 proteins was enriched in HPFH mice (5.8-fold, 5.2-fold and 2.7-fold, respectively), a result that concurs with a recent study in cell lines showing that these proteins form a complex with GATA-1 to mediate long-range interactions between the locus control region and the (A)gamma-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)gamma-globin activation, in contrast to other hereditary persistence of fetal hemoglobin mutations that result in a loss of repression. The mice provide additional tools to study gamma-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin.2417697705National Institutes of Health [R01 HL111264, R01 DK100595, R01 DK081290]National Center for Research Resources of the National Institutes of Health [P20 RR021940]National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103549]Sao Paulo Research Foundation (FAPESP) [2014/17413-9]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)