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Leighton, L.

Publications and source records attributed to Leighton, L..

2 recordsLinked to original sources
bioRxiv2018

The DNA repair associated protein Gadd45g regulates the temporal coding of immediate early gene expression and is required for the consolidation of associative fear memory

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC=\"FIGDIR/small/265355_fig6.gif\" ALT=\"Figure 6\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@16a5a7forg.highwire.dtl.DTLVardef@15b53dborg.highwire.dtl.DTLVardef@de7376org.highwire.dtl.DTLVardef@6e6732_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual abstractC_FLOATNO C_FIG We have identified a member of the Growth arrest and DNA damage (Gadd45) family, Gadd45{gamma}, which is known to be involved in the regulation of DNA repair, as a key player in the formation of associative fear memory. Gadd45{gamma} regulates the temporal dynamics of learning-induced immediate early gene (IEG) expression in the prelimbic prefrontal cortex through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises 1) a first wave of IEG expression governed by DSBs followed by an increase in DNA methylation, and 2) a second wave of IEG expression associated with Gadd45{gamma} and active DNA demethylation at the same site, which is necessary for memory consolidation.\n\nSignificance statementHow does the pattern of immediate early gene (IEG) transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how GADD45{gamma}, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, GADD45{gamma} serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.

neuroscience↗
bioRxiv2017

A functional role for the epigenetic regulator ING1 in activity-induced gene expression in primary cortical neurons

Epigenetic regulation of activity-induced gene expression involves multiple levels of molecular interaction, including histone and DNA modifications, as well as mechanisms of DNA repair. Here we demonstrate that the genome-wide deposition of Inhibitor of growth family member 1 (ING1), which is a central epigenetic regulatory protein, is dynamically regulated in response to activity in primary cortical neurons. ING1 knockdown leads to decreased expression of genes related to synaptic plasticity, including the regulatory subunit of calcineurin, Ppp3r1. In addition, ING1 binding at a site upstream of the transcription start site (TSS) of Ppp3r1 depends on yet another group of neuroepigenetic regulatory proteins, the Piwi-like family, which are also involved in DNA repair. These findings provide new insight into a novel mode of activity-induced gene expression, which involves the interaction between different epigenetic regulatory mechanisms traditionally associated with gene repression and DNA repair.\n\nAuthor contributionsL.J.L., Q.Z., T.W.B and W.W. designed the experiments. N.K., A.K., X.L., C.D., S.L. and W.W. designed and assembled shRNA constructs. L.J.L., W.W., X.L., C.D., P.R.M., E.Z., and S.L. conducted experiments. Q.Z. and Y.W. analysed ChIP-seq data. L.J.L., Q.Z., and W.W. wrote the paper. All authors reviewed and edited the manuscript.\n\nConflicts of interestNone.

neuroscience↗