Proteasome regulates transcription-favoring histone methylation, acetylation and ubiquitination in long-term synaptic plasticity

Abstract

Histone modifications, such as lysine methylation, acetylation and ubiquitination, are epigenetic tags that shape the chromatin landscape and regulate transcription required for synaptic plasticity and memory. Here we show that transcription-promoting histone H3 trimethylated at lysine 4 (H3K4me3), histone H3 acetylated at lysine 9 and 14 (H3K9/14ac), and histone H2B monoubiquitinated at lysine 120 (H2BK120ub) are enhanced after the induction of long-lasting chemically-induced long-term potentiation (cLTP) in the murine hippocampus. While H3K4me3 and H3K9/14ac were transiently upregulated, H2BK120ub levels oscillated after cLTP induction. In addition, we present results showing that blocking the proteasome, a molecular complex specialized for targeted protein degradation, inhibited the upregulation of these epigenetic tags after cLTP. Thus, our study provides the initial steps towards understanding the role of the proteasome in regulating histone modifications critical for synaptic plasticity.

Building up and knocking down: An emerging role for epigenetics and proteasomal degradation in systems consolidation

“…Recent evidence demonstrates that the proteasome may be involved in regulating gene activity during LTP, as proteasomal inhibition prevents transcription-promoting histone marks from occurring (Bach et al, 2015). Finally, some evidence suggests that DNA methylation is also regulated by the proteasome through regulated degradation of DNA methyltransferase enzymes (Esteve et al, 2009), thus positioning the proteasome as a regulator of crucial epigenetic processes.…”

Accelerated Deficits of Spatial Learning and Memory Resulting From Prenatal Inflammatory Insult Are Correlated With Abnormal Phosphorylation and Methylation of Histone 3 in CD-1 Mice

“…In contrast to the effect of Hp on gene transcription, the consequences of H methylation (Hme) depend on the number and location of the relevant methyl groups (Bach et al, 2015). A growing number of studies have revealed that Hme is involved in memory formation.…”

Proteolysis, synaptic plasticity and memory

“…This investigation showed that H2BK120ub levels oscillate after the induction of cLTP: an increase in histone H2B monoubiquitination was observed immediately after cLTP induction and at 30 min after cLTP induction, but not at 15 min (Bach et al, 2015). This finding is consistent with previous studies of histone H2B monoubiquitination in yeast transcriptional regulation, where multiple rounds of histone ubiquitination and deubiquitination are required for transcription initiation and elongation, respectively (Minsky et al, 2008; Weake and Workman, 2008; Wyce et al, 2007).…”

“…For example, a novel role of the proteasome in modulation of epigenetic histone modifications was described. This study demonstrated that trimethylation of histone 3 at lysine 4 (H3K4me3), acetylation of histone H3 at lysines 9 and 14 (H3K9/14ac), and monoubiquitination of histone H2B at lysine 120 (H2BK120ub) are enhanced immediately after cLTP induction and their enhancement is blocked by β-lactone pretreatment (Bach et al, 2015). …”

“…The Bach et al study reported that these modifications were dynamic. They showed that both H3K4me3 and H3K9/14ac were upregulated soon after cLTP induction and returned to baseline after 30 min (Bach et al, 2015). The experiments reported earlier described histone modifications that lasted hours or days after synaptic stimulation or behavioral training (Gupta-Agarwal et al, 2012; Levenson et al, 2004).…”