MIR29B mediates epigenetic mechanisms of HBG gene activation

Athena Starlard-Davenport, Alana Smith, Luan Vu, Biaoru Li, Betty Sue Pace

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Sickle cell disease (SCD) affects over 2 million people worldwide with high morbidity and mortality in underdeveloped countries. Therapeutic interventions aimed at reactivating fetal haemoglobin (HbF) is an effective approach for improving survival and ameliorating the clinical severity of SCD. A class of agents that inhibit DNA methyltransferase (DNMT) activity show promise as HbF inducers because off-target effects are not observed at low concentrations. However, these compounds are rapidly degraded by cytidine deaminase when taken by oral administration, creating a critical barrier to clinical development for SCD. We previously demonstrated that microRNA29B (MIR29B) inhibits de novo DNMT synthesis, therefore, the goal of our study was to determine if MIR29 mediates HbF induction. Overexpression of MIR29B in human KU812 cells and primary erythroid progenitors significantly increased the percentage of HbF positive cells, while decreasing the expression of DNMT3A and the HBG repressor MYB. Furthermore, HBG promoter methylation levels decreased significantly following MIR29B overexpression in human erythroid progenitors. We subsequently, observed higher MIR29B expression in SCD patients with higher HbF levels compared to those with low HbF. Our findings provide evidence for the ability of MIR29B to induce HbF and supports further investigation to expand treatment options for SCD.

Original languageEnglish (US)
Pages (from-to)91-100
Number of pages10
JournalBritish Journal of Haematology
Volume186
Issue number1
DOIs
StatePublished - Jul 1 2019

Fingerprint

Sickle Cell Anemia
Epigenomics
Transcriptional Activation
Methyltransferases
Cytidine Deaminase
Fetal Hemoglobin
Erythroid Precursor Cells
DNA
Methylation
Oral Administration
Morbidity
Survival
Mortality
Therapeutics

Keywords

  • DNA methylation
  • HBG
  • MIR29B
  • MYB
  • fetal haemoglobin

ASJC Scopus subject areas

  • Hematology

Cite this

MIR29B mediates epigenetic mechanisms of HBG gene activation. / Starlard-Davenport, Athena; Smith, Alana; Vu, Luan; Li, Biaoru; Pace, Betty Sue.

In: British Journal of Haematology, Vol. 186, No. 1, 01.07.2019, p. 91-100.

Research output: Contribution to journalArticle

Starlard-Davenport, Athena ; Smith, Alana ; Vu, Luan ; Li, Biaoru ; Pace, Betty Sue. / MIR29B mediates epigenetic mechanisms of HBG gene activation. In: British Journal of Haematology. 2019 ; Vol. 186, No. 1. pp. 91-100.
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