Live-cell epigenome manipulation by synthetic histone acetylation catalyst system

Area of Science:

• Epigenetics
• Chemical Biology
• Molecular Biology

Background:

• Histone modifications like acetylation and ubiquitination are crucial for epigenetic gene regulation.
• Altering the epigenome is a promising therapeutic and research strategy.
• A purely chemical method for inducing histone modifications in vivo is currently lacking.

Purpose of the Study:

• To develop an unprecedented, entirely chemical method for introducing histone modifications in living cells.
• To investigate the potential of a novel chemical catalyst for regioselective histone acetylation.
• To explore the impact of synthetic histone acetylation on physiological ubiquitination and chromatin functions.

Main Methods:

• Development of a chemical catalyst, PEG-LANA-DSSMe 11, designed to bind the nucleosome's acidic patch.
• Utilizing the catalyst for regioselective, synthetic histone acetylation at H2BK120 in living cells.
• Investigating the role of polyethylene glycol size in catalyst efficacy, stability, and binding affinity.

Main Results:

• The chemical catalyst PEG-LANA-DSSMe 11 successfully induced synthetic histone acetylation at H2BK120 in living cells.
• Catalyst performance was critically dependent on the size of its polyethylene glycol component.
• Synthetic acetylation suppressed physiological H2B ubiquitination, affecting chromatin functions like transcription and DNA damage response.

Conclusions:

• A novel chemical catalyst enables synthetic histone acetylation in living cells without genetic manipulation.
• This chemical approach provides a new tool for manipulating the epigenome.
• The catalyst facilitates the study of epigenetic mechanisms and their role in cellular processes.