Academic Journal
Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea
| العنوان: | Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea |
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| المؤلفون: | Vasiliki Chondrou, Eleana F. Stavrou, Georgios Markopoulos, Alexandra Kouraklis-Symeonidis, Vasilios Fotopoulos, Argiris Symeonidis, Efthymia Vlachaki, Panagiota Chalkia, George P. Patrinos, Adamantia Papachatzopoulou, Argyro Sgourou |
| المصدر: | Human Genomics, Vol 12, Iss 1, Pp 1-14 (2018) |
| بيانات النشر: | BMC |
| سنة النشر: | 2018 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | SCA homozygotes, SCA/β-thal heterozygotes, Hydroxyurea treatment, HbF induction, HBB cluster “modifying genes”, Epigenetic regulation, Medicine, Genetics, QH426-470 |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1479-7364 |
| Relation: | http://link.springer.com/article/10.1186/s40246-018-0177-z; https://doaj.org/toc/1479-7364; https://doaj.org/article/7ba168acd2004aafb36e8c68d294d210 |
| DOI: | 10.1186/s40246-018-0177-z |
| الاتاحة: | https://doi.org/10.1186/s40246-018-0177-z https://doaj.org/article/7ba168acd2004aafb36e8c68d294d210 |
| رقم الانضمام: | edsbas.68FFE8DC |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14797364 |
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| DOI: | 10.1186/s40246-018-0177-z |