Pathway: Regulation of NPAS4 gene transcription
Reactions in pathway: Regulation of NPAS4 gene transcription :
Regulation of NPAS4 gene transcription
Transcription of the NPAS4 gene is positively regulated by neuronal stimulation-related increase in intracellular calcium levels (Lin et al. 2008; Zhang et al. 2009, Mellström et al. 2014; Lobos et al. 2021).
In the absence of neuronal activity induced calcium influx, KCNIP3 (DREAM) binds to the promoter of the NPAS4 gene and represses NPAS4 transcription (Mellström et al. 2014). In non-neuronal cells, REST protein represses transcription of the NPAS4 gene (Bersten et al. 2014). In neuronal cells, REST may have a dual effect on NPAS4 expression: acting as a positive regulator of NPAS4 transcription early upon neuronal excitation and as a negative regulator at later time points, allowing NPAS4 to return to basal levels (Prestigio et al. 2021). Binding of agonist activated glucocorticoid receptor NR3C1 (also known as GR) to evolutionarily conserved glucocorticoid response elements (GREs) upstream of the NPAS4 gene transcription start site is responsible for stress-induced repression of NPAS4 gene transcription (Furukawa Hibi et al. 2012). Chronic restraint stress as well as corticosterone injection also reduce Npas4 gene expression in the mouse hippocampus (Yun et al. 2010). Though mechanisms remain to be delineated, HDAC5 was reported by multiple studies to contribute to NPAS4 gene repression (Taniguchi et al. 2017, Hashikawa-Hobara et al. 2021; Lv et al. 2021; Rein et al. 2022). In addition, HDAC3 was reported as the NPAS4 gene repressor during neurodegeneration (Louis Sam Titus et al. 2019).
SRF (Serum response factor) stimulates NPAS4 gene transcription upon neuronal excitation (Kuzniewska et al. 2016, Lösing et al. 2017, Förstner and Knöll 2019). NPAS4 gene transcription is positively regulated by PI3K/AKT signaling (Ooe et al. 2009; Speckmann et al. 2016), and only partially dependent on ERK (MAPK) signaling (Blüthgen et al. 2017). NPAS4 may be one of the EGR1 target genes (Han et al. 2014). Neuronal activity stimulation may trigger the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including FOS, NPAS4, and EGR1, which may contribute to their transcriptional activation (Madabushi et al. 2015). NPAS4 appears to be a downstream target involved in amyloid precursor protein (APP)-dependent regulation of inhibitory synaptic transmission (Opsomer et al. 2020). TET1, a methylcytosine dioxygenase that catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promotes DNA demethylation is implicated in transcriptional activation of NPAS4 gene through demethylation of hypermethylated CpG dinucleotides in the NPAS4 gene promoter region (Rudenko et al. 2013). Transcriptional activation of the NPAS4 gene is associated with the appearance of H3K4me3 mark and 5hmC mark at the NPAS4 gene promoter (Webb et al. 2017).
In the absence of neuronal activity induced calcium influx, KCNIP3 (DREAM) binds to the promoter of the NPAS4 gene and represses NPAS4 transcription (Mellström et al. 2014). In non-neuronal cells, REST protein represses transcription of the NPAS4 gene (Bersten et al. 2014). In neuronal cells, REST may have a dual effect on NPAS4 expression: acting as a positive regulator of NPAS4 transcription early upon neuronal excitation and as a negative regulator at later time points, allowing NPAS4 to return to basal levels (Prestigio et al. 2021). Binding of agonist activated glucocorticoid receptor NR3C1 (also known as GR) to evolutionarily conserved glucocorticoid response elements (GREs) upstream of the NPAS4 gene transcription start site is responsible for stress-induced repression of NPAS4 gene transcription (Furukawa Hibi et al. 2012). Chronic restraint stress as well as corticosterone injection also reduce Npas4 gene expression in the mouse hippocampus (Yun et al. 2010). Though mechanisms remain to be delineated, HDAC5 was reported by multiple studies to contribute to NPAS4 gene repression (Taniguchi et al. 2017, Hashikawa-Hobara et al. 2021; Lv et al. 2021; Rein et al. 2022). In addition, HDAC3 was reported as the NPAS4 gene repressor during neurodegeneration (Louis Sam Titus et al. 2019).
SRF (Serum response factor) stimulates NPAS4 gene transcription upon neuronal excitation (Kuzniewska et al. 2016, Lösing et al. 2017, Förstner and Knöll 2019). NPAS4 gene transcription is positively regulated by PI3K/AKT signaling (Ooe et al. 2009; Speckmann et al. 2016), and only partially dependent on ERK (MAPK) signaling (Blüthgen et al. 2017). NPAS4 may be one of the EGR1 target genes (Han et al. 2014). Neuronal activity stimulation may trigger the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including FOS, NPAS4, and EGR1, which may contribute to their transcriptional activation (Madabushi et al. 2015). NPAS4 appears to be a downstream target involved in amyloid precursor protein (APP)-dependent regulation of inhibitory synaptic transmission (Opsomer et al. 2020). TET1, a methylcytosine dioxygenase that catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promotes DNA demethylation is implicated in transcriptional activation of NPAS4 gene through demethylation of hypermethylated CpG dinucleotides in the NPAS4 gene promoter region (Rudenko et al. 2013). Transcriptional activation of the NPAS4 gene is associated with the appearance of H3K4me3 mark and 5hmC mark at the NPAS4 gene promoter (Webb et al. 2017).
RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation.
The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template.
The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template.
Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.