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

      Abstract

      Background

      Posttranslational histone modifications play a critical role in the regulation of gene transcription underlying synaptic plasticity and memory formation. One such epigenetic change is histone ubiquitination, a process that is mediated by the ubiquitin–proteasome system in a manner similar to that by which proteins are normally targeted for degradation. However, histone ubiquitination mechanisms are poorly understood in the brain and in learning. In this article, we describe a new role for the ubiquitin–proteasome system in histone crosstalk, showing that learning-induced monoubiquitination of histone H2B (H2Bubi) is required for increases in the transcriptionally active H3 lysine 4 trimethylation (H3K4me3) mark at learning-related genes in the hippocampus.

      Methods

      Using a series of molecular, biochemical, electrophysiological, and behavioral experiments, we interrogated the effects of short interfering RNA–mediated knockdown and CRISPR (clustered regularly interspaced short palindromic repeats)-mediated upregulation of ubiquitin ligases, deubiquitinating enzymes and histone methyltransferases in the rat dorsal hippocampus during memory consolidation.

      Results

      We show that H2Bubi recruits H3K4me3 through a process that is dependent on the 19S proteasome subunit RPT6 and that a loss of H2Bubi in the hippocampus prevents learning-induced increases in H3K4me3, gene transcription, synaptic plasticity, and memory formation. Furthermore, we show that CRISPR–dCas9-mediated increases in H2Bubi promote H3K4me3 and memory formation under weak training conditions and that promoting histone methylation does not rescue memory impairments resulting from loss of H2Bubi.

      Conclusions

      These results suggest that H2B ubiquitination regulates histone crosstalk in learning by way of nonproteolytic proteasome function, demonstrating a novel mechanism by which histone modifications are coordinated in response to learning.

      Keywords

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      References

        • Jarome T.J.
        • Lubin F.D.
        Epigenetic mechanisms of memory formation and reconsolidation.
        Neurobiol Learn Mem. 2014; 115: 116-127
        • Kwapis J.L.
        • Wood M.A.
        Epigenetic mechanisms in fear conditioning: Implications for treating post-traumatic stress disorder.
        Trends Neurosci. 2014; 37: 706-720
        • Dias B.G.
        • Maddox S.A.
        • Klengel T.
        • Ressler K.J.
        Epigenetic mechanisms underlying learning and the inheritance of learned behaviors.
        Trends Neurosci. 2015; 38: 96-107
        • Haettig J.
        • Stefanko D.P.
        • Multani M.L.
        • Figueroa D.X.
        • McQuown S.C.
        • Wood M.A.
        HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner.
        Learn Mem. 2011; 18: 71-79
        • McQuown S.C.
        • Barrett R.M.
        • Matheos D.P.
        • Post R.J.
        • Rogge G.A.
        • Alenghat T.
        • et al.
        HDAC3 is a critical negative regulator of long-term memory formation.
        J Neurosci. 2011; 31: 764-774
        • Day J.J.
        • Sweatt J.D.
        DNA methylation and memory formation.
        Nat Neurosci. 2010; 13: 1319-1323
        • Gupta-Agarwal S.
        • Franklin A.V.
        • Deramus T.
        • Wheelock M.
        • Davis R.L.
        • McMahon L.L.
        • et al.
        G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation.
        J Neurosci. 2012; 32: 5440-5453
        • Gupta-Agarwal S.
        • Jarome T.J.
        • Fernandez J.
        • Lubin F.D.
        NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation.
        Learn Mem. 2014; 21: 351-362
        • Gupta S.
        • Kim S.Y.
        • Artis S.
        • Molfese D.L.
        • Schumacher A.
        • Sweatt J.D.
        • et al.
        Histone methylation regulates memory formation.
        J Neurosci. 2010; 30: 3589-3599
        • Kerimoglu C.
        • Agis-Balboa R.C.
        • Kranz A.
        • Stilling R.
        • Bahari-Javan S.
        • Benito-Garagorri E.
        • et al.
        Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice.
        J Neurosci. 2013; 33: 3452-3464
        • Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium
        Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.
        Nat Neurosci. 2015; 18: 199-209
        • Miller C.A.
        • Campbell S.L.
        • Sweatt J.D.
        DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity.
        Neurobiol Learn Mem. 2008; 89: 599-603
        • Sun Z.W.
        • Allis C.D.
        Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.
        Nature. 2002; 418: 104-108
        • Jarome T.J.
        • Helmstetter F.J.
        The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation.
        Neurobiol Learn Mem. 2013; 105: 107-116
        • Hegde A.N.
        The ubiquitin-proteasome pathway and synaptic plasticity.
        Learn Mem. 2010; 17: 314-327
        • Wojcik F.
        • Dann G.P.
        • Beh L.Y.
        • Debelouchina G.T.
        • Hofmann R.
        • Muir T.W.
        Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants.
        Nat Commun. 2018; 9: 1394
        • Shema E.
        • Tirosh I.
        • Aylon Y.
        • Huang J.
        • Ye C.
        • Moskovits N.
        • et al.
        The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression.
        Genes Dev. 2008; 22: 2664-2676
        • Wang E.
        • Kawaoka S.
        • Yu M.
        • Shi J.
        • Ni T.
        • Yang W.
        • et al.
        Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia.
        Proc Natl Acad Sci U S A. 2013; 110: 3901-3906
        • Jarome T.J.
        • Butler A.A.
        • Nichols J.N.
        • Pacheco N.L.
        • Lubin F.D.
        NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.
        Front Mol Neurosci. 2015; 8: 54
        • Jarome T.J.
        • Perez G.A.
        • Hauser R.M.
        • Hatch K.M.
        • Lubin F.D.
        EZH2 methyltransferase activity controls Pten expression and mTOR signaling during fear memory reconsolidation.
        J Neurosci. 2018; 38: 7635-7648
        • Webb W.M.
        • Sanchez R.G.
        • Perez G.
        • Butler A.A.
        • Hauser R.M.
        • Rich M.C.
        • et al.
        Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory.
        Neurobiol Learn Mem. 2017; 142: 66-78
        • Gertz J.
        • Savic D.
        • Varley K.E.
        • Partridge E.C.
        • Safi A.
        • Jain P.
        • et al.
        Distinct properties of cell-type-specific and shared transcription factor binding sites.
        Mol Cell. 2013; 52: 25-36
        • Bernstein B.E.
        • Stamatoyannopoulos J.A.
        • Costello J.F.
        • Ren B.
        • Milosavljevic A.
        • Meissner A.
        • et al.
        The NIH Roadmap Epigenomics Mapping Consortium.
        Nat Biotechnol. 2010; 28: 1045-1048
        • Ma M.K.
        • Heath C.
        • Hair A.
        • West A.G.
        Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity.
        PLoS Genet. 2011; 7e1002175
        • Ezhkova E.
        • Tansey W.P.
        Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3.
        Mol Cell. 2004; 13: 435-442
        • Zheng Y.
        • Shen W.
        • Zhang J.
        • Yang B.
        • Liu Y.N.
        • Qi H.
        • et al.
        CRISPR interference-based specific and efficient gene inactivation in the brain.
        Nat Neurosci. 2018; 21: 447-454
        • Stefanko D.P.
        • Barrett R.M.
        • Ly A.R.
        • Reolon G.K.
        • Wood M.A.
        Modulation of long-term memory for object recognition via HDAC inhibition.
        Proc Natl Acad Sci U S A. 2009; 106: 9447-9452
        • Bredy T.W.
        • Wu H.
        • Crego C.
        • Zellhoefer J.
        • Sun Y.E.
        • Barad M.
        Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear.
        Learn Mem. 2007; 14: 268-276
        • Feng J.
        • Zhou Y.
        • Campbell S.L.
        • Le T.
        • Li E.
        • Sweatt J.D.
        • et al.
        Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.
        Nat Neurosci. 2010; 13: 423-430
        • Guan J.S.
        • Haggarty S.J.
        • Giacometti E.
        • Dannenberg J.H.
        • Joseph N.
        • Gao J.
        • et al.
        HDAC2 negatively regulates memory formation and synaptic plasticity.
        Nature. 2009; 459: 55-60
        • Tweedie-Cullen R.Y.
        • Reck J.M.
        • Mansuy I.M.
        Comprehensive mapping of post-translational modifications on synaptic, nuclear, and histone proteins in the adult mouse brain.
        J Proteome Res. 2009; 8: 4966-4982
        • Batta K.
        • Zhang Z.
        • Yen K.
        • Goffman D.B.
        • Pugh B.F.
        Genome-wide function of H2B ubiquitylation in promoter and genic regions.
        Genes Dev. 2011; 25: 2254-2265
        • Bourbousse C.
        • Ahmed I.
        • Roudier F.
        • Zabulon G.
        • Blondet E.
        • Balzergue S.
        • et al.
        Histone H2B monoubiquitination facilitates the rapid modulation of gene expression during Arabidopsis photomorphogenesis.
        PLoS Genet. 2012; 8e1002825
        • Jarome T.J.
        • Werner C.T.
        • Kwapis J.L.
        • Helmstetter F.J.
        Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala.
        PLoS One. 2011; 6e24349
        • Reis D.S.
        • Jarome T.J.
        • Helmstetter F.J.
        Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex.
        Front Behav Neurosci. 2013; 7: 150
        • Artinian J.
        • McGauran A.M.
        • De Jaeger X.
        • Mouledous L.
        • Frances B.
        • Roullet P.
        Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation.
        Eur J Neurosci. 2008; 27: 3009-3019
        • Lopez-Salon M.
        • Alonso M.
        • Vianna M.R.
        • Viola H.
        • Mello e Souza T.
        • Izquierdo I.
        • et al.
        The ubiquitin-proteasome cascade is required for mammalian long-term memory formation.
        Eur J Neurosci. 2001; 14: 1820-1826
        • Pavlopoulos E.
        • Trifilieff P.
        • Chevaleyre V.
        • Fioriti L.
        • Zairis S.
        • Pagano A.
        • et al.
        Neuralized1 activates CPEB3: A function for nonproteolytic ubiquitin in synaptic plasticity and memory storage.
        Cell. 2011; 147: 1369-1383
        • Ohnishi Y.H.
        • Ohnishi Y.N.
        • Nakamura T.
        • Ohno M.
        • Kennedy P.J.
        • Yasuyuki O.
        • et al.
        PSMC5, a 19S proteasomal ATPase, regulates cocaine action in the nucleus accumbens.
        PLoS One. 2015; 10e126710
        • Zhang Z.
        • Jones A.
        • Joo H.Y.
        • Zhou D.
        • Cao Y.
        • Chen S.
        • et al.
        USP49 deubiquitinates histone H2B and regulates cotranscriptional pre-mRNA splicing.
        Genes Dev. 2013; 27: 1581-1595
        • Keiser A.A.
        • Wood M.A.
        Examining the contribution of histone modification to sex differences in learning and memory.
        Learn Mem. 2019; 26: 318-331
        • Ramzan F.
        • Creighton S.D.
        • Hall M.
        • Baumbach J.
        • Wahdan M.
        • Poulson S.J.
        • et al.
        Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain.
        Sci Rep. 2020; 10: 14331
        • Lopez-Atalaya J.P.
        • Ciccarelli A.
        • Viosca J.
        • Valor L.M.
        • Jimenez-Minchan M.
        • Canals S.
        • et al.
        CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement.
        EMBO J. 2011; 30: 4287-4298
        • Frick K.M.
        Epigenetics, oestradiol and hippocampal memory consolidation.
        J Neuroendocrinol. 2013; 25: 1151-1162
        • Maurice T.
        • Duclot F.
        • Meunier J.
        • Naert G.
        • Givalois L.
        • Meffre J.
        • et al.
        Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice.
        Neuropsychopharmacology. 2008; 33: 1584-1602
        • Devulapalli R.K.
        • Nelsen J.L.
        • Orsi S.A.
        • McFadden T.
        • Navabpour S.
        • Jones N.
        • et al.
        Males and females differ in the subcellular and brain region dependent regulation of proteasome activity by CaMKII and protein kinase A.
        Neuroscience. 2019; 418: 1-14
        • Jarome T.J.
        • Lubin F.D.
        Histone lysine methylation: Critical regulator of memory and behavior.
        Rev Neurosci. 2013; 24: 375-387
        • Parkel S.
        • Lopez-Atalaya J.P.
        • Barco A.
        Histone H3 lysine methylation in cognition and intellectual disability disorders.
        Learn Mem. 2013; 20: 570-579