EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression

Area of Science:

• Epigenetics
• Hematology
• Molecular Biology

Background:

• Fetal hemoglobin (HbF) induction is a proven treatment for sickle cell disease (SCD).
• Histone methyltransferases EHMT1 and EHMT2 are implicated in gene silencing via H3K9 methylation.
• Understanding the epigenetic regulation of γ-globin is crucial for developing novel SCD therapies.

Purpose of the Study:

• To investigate the role of EHMT1/2 in regulating γ-globin expression.
• To evaluate UNC0638, an EHMT1/2 inhibitor, as a potential therapeutic agent for SCD.
• To explore the epigenetic mechanisms underlying γ-globin gene silencing.

Main Methods:

• Small-molecule screening to identify compounds inducing γ-globin.
• In vitro studies using primary human erythroid cells and murine erythroleukemia cells.
• Gene knockdown (shRNA) and knockout (CRISPR/Cas9) of EHMT1/2.
• Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq).

Main Results:

• UNC0638 selectively inhibits EHMT1/2 and significantly increases γ-globin expression and HbF synthesis in human erythroid cells.
• EHMT1/2 inhibition or knockdown leads to reduced H3K9 dimethylation and increased H3K9 acetylation at the γ-globin locus.
• UNC0638 treatment did not adversely affect cell morphology, proliferation, or differentiation.
• Combination therapy with entinostat or decitabine further enhanced γ-globin induction.

Conclusions:

• EHMT1 and EHMT2 are key epigenetic repressors of γ-globin expression.
• Targeting EHMT1/2 with inhibitors like UNC0638 is a promising novel therapeutic strategy for SCD.
• Epigenetic modulation of H3K9 methylation represents a viable approach to increase HbF levels in SCD patients.