Biology subjects

Zajaczkowski, E. L.

Publications and source records attributed to Zajaczkowski, E. L..

5 recordsLinked to original sources

bioRxiv2025

A mobile circular DNA element drives memory-related processes in mice

Extrachromosomal circular DNAs (ecDNAs) are double stranded, closed loop DNA molecules that act independently of the genome. Here we report the discovery of a brain-enriched ecDNA, ecCldn34d, that regulates the transcriptional state of plasticity-related genes and is temporally associated with the stability of fear memories. ecDNA therefore represents a novel class of mobile DNA elements that are involved in experience-dependent neuroadaptation.

neuroscience↗

bioRxiv2022

Inhibiting circRNA Cdr1as expression in the ILPFC of adult male C57BL/6J mice impairs fear extinction memory

Circular RNAs (circRNAs) comprise a novel class of regulatory RNAs that are abundant in the brain, particularly within synapses. They are highly stable, dynamically regulated, and display a range of functional roles, including as decoys for miRNAs and proteins and, in some cases, translation. Early work in animal models revealed an association between circRNAs and neurodegenerative and neuropsychiatric disorders; however, relatively few studies have shown a causal link between circRNA function and memory. To address this knowledge gap, we sequenced circRNAs in the synaptosome compartment of the medial prefrontal cortex of fear extinction trained male C57BL/6J mice and found 12837 circRNAs enriched at the synapse, including Cdr1as. Targeted knockdown of Cdr1as in the neural processes of the infralimbic prefrontal cortex of male C57BL/6J mice led to impaired fear extinction memory. Altogether, our findings highlight the importance of localised circRNA activity at the synapse for memory formation and suggest that circRNAs may have a more widespread effect on brain function than previously thought.

neuroscience↗

bioRxiv2022

Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory

The RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.

neuroscience↗

bioRxiv2018

Hippocampal knockdown of Piwil1 and Piwil2 enhances contextual fear memory in mice

The Piwi pathway is a conserved gene regulatory mechanism comprised of Piwi-like proteins and Piwi-interacting RNAs, which modulates gene expression via RNA interference and epigenetic mechanisms. The mammalian Piwi pathway has been defined by its role in transposon control during spermatogenesis, and despite an increasing number of studies demonstrating its expression in the nervous system, relatively little is known about its function in neurons or potential contribution to gene regulation in the brain. We have discovered that all three Piwi-like genes are expressed in several regions of the mouse brain, and that simultaneous knockdown of Piwil1 and Piwil2 in the adult mouse hippocampus enhances contextual fear memory without affecting generalised anxiety. Our results implicate the Piwi pathway in control of plasticity-related gene expression in the adult mammalian brain.

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↗