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Transcriptomic screen to identify genes regulated by dSET2 in Drosophila third-instar larval nervous system

ABSTRACT: Gene expression changes in neurons are primarily thought to occur via activity driven transcription of immediate-early genes (Chen et al., 2016). Little notice is given to how intracellular Ca2+ changes downstream of myriad signaling pathways affects neuronal gene expression. We recently identified a set of genes whose expression requires IP3R/Ca2+ signals in larval neurons (Jayakumar et al., 2018). This work studies how IP3R/Ca2+ signals regulate changes in gene expression, critical to growth and development, through the histone methyltransferase dSET2. In this study we investigate how IP3R and dSET2 regulate a common set of developmentally significant genes to enable the larval to pupal transition on a protein deprived diet.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE162094 | GEO | 2020/11/25

REPOSITORIES: GEO

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Project description:Many addictive drugs such as nicotine mediate reward and reinforcing mechanisms within the mesolimbic pathway involving midbrain dopaminergic (mDA) neurons via nicotinic acetylcholine receptors (nAChRs). Previously, genome-wide association analyses (GWAs) identified several nucleotide polymorphism (SNP) associated with increased risk of addictive phenotypes including the nonsynonymous rs16969968 SNP encoding D398->N398 variation in the CHRNA5 gene (Bierut et al., 2008; Saccone et al., 2007) . However, the etiology and the pathophysiology associated with the N398 allele is unknown. Previous animal studies using a knock-in of human CHRNA5 N398 revealed increased nicotine consumption. However, given the evolutionary distance between mice and humans, identifying intrinsic factors that affect addiction may correlate poorly, limiting the conclusiveness of these studies. In this study, induced pluripotent stem cell (iPSC) lines were derived from cryopreserved lymphocytes drawn from patients with homozygous minor alleles (N398) of rs16969968 and demonstrated nicotine addiction as well as age- and gender-matched unaffected controls carrying the major allele (D398). Cultures of primarily mDA neurons were prepared from these iPSC lines. Gene expression analysis using RT-PCR and RNAseq revealed similar expression of mRNAs encoding subunits of nAChR in mDA neurons derived from both D398 and N398 iPSC lines, however, gene ontology (GO) analysis revealed an increased enrichment of genes associated with neuroactive ligand-receptor interactions and Ca2+ signaling pathways in N398 neurons. Moreover, the N398 neuronal population responded more actively to application of nicotine in both electrophysiological analysis and Ca2+-imaging analysis. Together, these results suggest that the N398 variation affects Ca2+-signaling in neurons, which may explain the predisposition of subjects carrying this mutation for addictive behavior in subjects carrying the nonsynonymous rs16969968 SNP (Sherva et al., 2008).

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Transcriptomic screen to identify genes regulated by dSET2 in Drosophila third-instar larval nervous system

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