Designer Catalyst-Enabled Regiodivergent Histone Acetylation

Area of Science:

• Epigenetics and Molecular Biology
• Chromatin Biology
• Chemical Biology

Background:

• The histone code, a system of histone post-translational modifications (PTMs), governs chromatin structure and gene expression.
• Understanding the functional impact of specific PTMs requires tools for precise modification introduction in living cells.

Purpose of the Study:

• To design and develop regioselective catalysts for targeted histone acetylation on specific lysine residues of histone H2B.
• To elucidate the design principles governing regioselectivity in histone modification catalysts.
• To investigate the cellular and molecular consequences of distinct histone H2B acetylation patterns.

Main Methods:

• Utilized molecular dynamics simulations to analyze catalyst-nucleosome interactions.
• Employed systematic experimental optimization to refine catalyst structures for regioselectivity.
• Conducted biochemical and cellular assays to assess the effects of targeted histone acetylation.

Main Results:

• Developed three regioselective catalysts targeting distinct lysine residues (K43, K108, K120) on histone H2B.
• Identified key design principles for regioselectivity, emphasizing exclusion of off-target residues from the catalyst effective region.
• Demonstrated that specific lysine acetylations on H2B uniquely influence nucleosome-interacting molecule binding, transcriptional programs, and cellular phenotypes.

Conclusions:

• Established a framework for designing regioselective histone acetylation catalysts.
• Advanced the understanding of how specific histone PTMs regulate gene expression and cellular processes.
• Provided novel tools for dissecting the functional roles of the histone code in epigenetics.