Evidence map›Paper›PMID 30285874›Full record

ArticleHuman genomics2018

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

Vasiliki Chondrou, Eleana F Stavrou, Georgios Markopoulos, Alexandra Kouraklis-Symeonidis, Vasilios Fotopoulos, Argiris Symeonidis, Efthymia Vlachaki, Panagiota Chalkia, George P Patrinos, Adamantia Papachatzopoulou and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human genomics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.0field-weighted citation impact, top 23% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 26 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. LRF Promotes Indirectly Advantageous Chromatin Conformation viaInternational journal of molecular sciences · 2022
    Article
  5. Review
  6. Exploring epigenetic and microRNA approaches for γ-globin gene regulation.Experimental biology and medicine (Maywood, N.J.) · 2021
    Review
  7. Article
  8. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 6 institutions in 1 country.

Vasiliki ChondrouSchool of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece.
Eleana F StavrouSchool of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece.
Georgios MarkopoulosFaculty of Medicine, Biology Laboratory, University of Ioannina, Ioannina, Greece.
Alexandra Kouraklis-SymeonidisThalassemia and Hemoglobinopathies Unit, Hematology Division, Department of Internal Medicine, General University Hospital of Patras, Patras, Greece.
Vasilios FotopoulosSchool of Science and Technology, Digital Systems and Media Computing Laboratory, Hellenic Open University, Patras, Greece.
Argiris SymeonidisMedical School, Hematology Division, Department of Internal Medicine, University of Patras, Patras, Greece.
Efthymia VlachakiThalassemia Unit, "Hippokrateio" General Hospital of Thessaloniki, Thessaloniki, Greece.
Panagiota ChalkiaThalassemia and Sickle Cell Unit, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece.
George P PatrinosSchool of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras, Patras, Greece.
Adamantia PapachatzopoulouMedical Faculty, Laboratory of General Biology, University of Patras, Patras, Greece.
Argyro SgourouSchool of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece. sgourou@eap.gr.
Hellenic Open University · GRUniversity of Patras · GRAHEPA University Hospital · GRGeneral University Hospital of Patras · GRIppokrateio General Hospital of Thessaloniki · GRUniversity of Ioannina · GR

Funding

European Commission 668353
6 · The paper itself

Abstract

backgroundWe 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.

resultsWe 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.

conclusionsThis 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.

Indexed as

Anemia, Sickle Cellbeta-Globinsbeta-ThalassemiaCarrier ProteinsDNA-Binding ProteinsDNA MethylationFemaleGATA2 Transcription FactorGene Expression RegulationHeterozygoteHumansHydroxyureaKruppel-Like Transcription FactorsMaleMAP Kinase Kinase Kinase 5Nuclear ProteinsBCL11A protein, humanbeta-GlobinsCarrier ProteinsDNA-Binding Proteinserythroid Kruppel-like factorGATA2 protein, humanGATA2 Transcription FactorHydroxyureaKruppel-Like Transcription FactorsMAP3K5 protein, humanMAP Kinase Kinase Kinase 5Nuclear ProteinsRepressor ProteinsSIN3A transcription factorSin3 Histone Deacetylase and Corepressor ComplexTranscription FactorsZBTB7A protein, humanEpigenetic regulationHBB cluster “modifying genes”HbF inductionHydroxyurea treatmentSCA homozygotesSCA/β-thal heterozygotes

Identifiers

PMID30285874
PMCPMC6167880
OpenAlexW2893667625

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.