Ubiquitination of Histone H2B by Proteasome Subunit RPT6 Controls Histone Methylation Chromatin Dynamics During...

Area of Science:

• Neuroscience
• Epigenetics
• Molecular Biology

Background:

• Posttranslational histone modifications regulate gene transcription essential for synaptic plasticity and memory.
• Histone ubiquitination, a key epigenetic mechanism, is poorly understood in the context of brain function and learning.
• This study investigates the role of the ubiquitin-proteasome system in histone crosstalk during memory formation.

Purpose of the Study:

• To elucidate the role of histone H2B monoubiquitination (H2Bubi) in learning-induced gene transcription.
• To determine the mechanism by which H2Bubi influences other histone modifications, specifically H3K4me3.
• To establish the necessity of H2Bubi for synaptic plasticity and memory consolidation.

Main Methods:

• Utilized short interfering RNA (siRNA) and CRISPR gene editing in rat dorsal hippocampus.
• Investigated the impact of modulating ubiquitin ligases, deubiquitinating enzymes, and histone methyltransferases.
• Employed molecular, biochemical, electrophysiological, and behavioral analyses.

Main Results:

• Learning-induced H2Bubi is essential for increased H3K4me3 marks at learning-related genes.
• H2Bubi recruits H3K4me3 via the 19S proteasome subunit RPT6.
• Loss of H2Bubi impaired learning-induced H3K4me3, gene transcription, synaptic plasticity, and memory formation.
• Enhanced H2Bubi promoted H3K4me3 and memory, while promoting histone methylation did not rescue H2Bubi loss-induced memory deficits.

Conclusions:

• H2B ubiquitination regulates histone crosstalk in learning through nonproteolytic proteasome function.
• This identifies a novel mechanism coordinating histone modifications during memory formation.
• H2Bubi is a critical epigenetic regulator of learning and memory.