Histone demethylase LSD1 is a folate-binding protein

Area of Science:

• Epigenetics
• Molecular Biology
• Biochemistry

Background:

• Histone methylation is a key epigenetic regulator of gene expression.
• Enzymatic removal of methyl groups from histones, particularly lysine 4 and 9 of histone 3, is crucial for gene regulation.
• Lysine-specific demethylase 1 (LSD1) was the first identified enzyme with this demethylase activity, producing formaldehyde.

Purpose of the Study:

• To investigate the association between LSD1 and folate.
• To characterize the binding affinity of different folate forms to LSD1.
• To explore the role of folate in histone demethylation and epigenetic gene control.

Main Methods:

• Nuclear extracts from HeLa cells were analyzed for LSD1-folate association.
• Back-scattering interferometry was employed to measure folate binding to LSD1 in solution.
• Binding affinities (Kd) of various folate forms to full-length and truncated LSD1 were determined.

Main Results:

• Nuclear extracts of HeLa cells contain LSD1 associated with folate.
• The natural pentaglutamate form of tetrahydrofolate (6R,S) exhibited the highest binding affinity to full-length LSD1 (Kd = 2.8 microM).
• Folate was shown to participate in the enzymatic demethylation process mediated by LSD1.

Conclusions:

• Folate is associated with LSD1, the primary enzyme responsible for demethylating histone 3 at lysines 4 and 9.
• The interaction between folate and LSD1 suggests a novel role for this micronutrient in the epigenetic regulation of gene expression.
• This finding opens new avenues for understanding how nutritional factors influence epigenetic mechanisms.