Nair, S. S. | bioRxiv Science

bioRxiv2018

Dopamine maintains network synchrony via direct modulation of gap junctions in the crustacean cardiac ganglion

Abstract The Large Cell (LC) motor neurons of the crab (C. borealis) cardiac ganglion have variable membrane conductance magnitudes even within the same individual, yet produce identical synchronized activity in the intact network. In our previous study (Lane et al., 2016) we blocked a subset of K+ conductances across LCs, resulting in loss of synchronous activity. In this study, we hypothesized that this same variability of conductances could make LCs vulnerable to desynchronization during neuromodulation. We exposed the LCs to serotonin (5HT) and dopamine (DA) while recording simultaneously from multiple LCs. Both amines had distinct excitatory effects on LC output, but only 5HT caused desynchronized output. We further determined that DA rapidly increased gap junctional conductance. Co-application of both amines induced 5HT-like output, but waveforms remained synchronized. Furthermore, DA prevented desynchronization induced by the K+ channel blocker tetraethylammonium (TEA), suggesting that dopaminergic modulation of electrical coupling plays a protective role in maintaining network synchrony.

neuroscience↗

bioRxiv2018

Replication timing shapes the cancer epigenome and the nature of chromosomal rearrangements

HighlightsO_LIReplication timing alterations are conserved in cancers of different cell origins\nC_LIO_LILong-range epigenetic deregulation in cancer involves altered replication timing\nC_LIO_LICancer late-replicating loci are hypomethylated and acquire facultative heterochromatin\nC_LIO_LIReplication timing status potentiates cis and trans chromosomal rearrangements\nC_LI\n\nSummaryReplication timing is known to facilitate the establishment of epigenome, however, the intimate connection between DNA replication timing and changes to the genome and epigenome in cancer remain uncharted. Here, we perform Repli-Seq and integrated epigenome analysis and show that early-replicating loci are predisposed to hypermethylation and late-replicating loci to hypomethylation, enrichment of H3K27me3 and concomitant loss of H3K9me3. We find that altered replication timing domains correspond to long-range epigenetically deregulated regions in prostate cancer, and a subset of these domains are remarkably conserved across cancers from different tissue origins. Analyses of 214 prostate and 35 breast cancer genomes reveal that late-replicating DNA is prone to cis and early-replicating DNA to trans chromosomal rearrangements. We propose that differences in epigenetic deregulation related to spatial and temporal positioning between early and late replication potentiate the landscape of chromosomal rearrangements in cancer.

genomics↗