Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea.

Autor: Chondrou V; School of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece., Stavrou EF; School of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece., Markopoulos G; Faculty of Medicine, Biology Laboratory, University of Ioannina, Ioannina, Greece., Kouraklis-Symeonidis A; Thalassemia and Hemoglobinopathies Unit, Hematology Division, Department of Internal Medicine, General University Hospital of Patras, Patras, Greece., Fotopoulos V; School of Science and Technology, Digital Systems and Media Computing Laboratory, Hellenic Open University, Patras, Greece., Symeonidis A; Medical School, Hematology Division, Department of Internal Medicine, University of Patras, Patras, Greece., Vlachaki E; Thalassemia Unit, 'Hippokrateio' General Hospital of Thessaloniki, Thessaloniki, Greece., Chalkia P; Thalassemia and Sickle Cell Unit, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece., Patrinos GP; School of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras, Patras, Greece., Papachatzopoulou A; Medical Faculty, Laboratory of General Biology, University of Patras, Patras, Greece., Sgourou A; School of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece. sgourou@eap.gr.
Jazyk: angličtina
Zdroj: Human genomics [Hum Genomics] 2018 Oct 01; Vol. 12 (1), pp. 45. Date of Electronic Publication: 2018 Oct 01.
DOI: 10.1186/s40246-018-0177-z
Abstrakt: Background: We aimed to clarify the emerging epigenetic landscape in a group of genes classified as "modifier genes" of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented.
Results: We examined the CpG islands' DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients' monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU.
Conclusions: This is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5' CpG sequences of all studied human HBB cluster "modifier genes." Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the β-type hemoglobinopathy patients.
Databáze: MEDLINE
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