Regulation of NPAS4 gene transcription

Stable Identifier
R-HSA-9768777
Type
Pathway
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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Regulation of NPAS4 gene transcription
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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).
Literature References
PubMed ID Title Journal Year
10078534 DREAM is a Ca2+-regulated transcriptional repressor

Carrión, AM, Link, WA, Ledo, F, Mellström, B, Naranjo, JR

Nature 1999
20626564 Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4

Yun, J, Koike, H, Ibi, D, Toth, E, Mizoguchi, H, Nitta, A, Yoneyama, M, Ogita, K, Yoneda, Y, Nabeshima, T, Nagai, T, Yamada, K

J Neurochem 2010
34855580 REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

Prestigio, C, Ferrante, D, Marte, A, Romei, A, Lignani, G, Onofri, F, Valente, P, Benfenati, F, Baldelli, P

Elife 2021
28349920 Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo

Blüthgen, N, van Bentum, M, Merz, B, Kuhl, D, Hermey, G

Sci Rep 2017
19680447 Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity

Zhang, SJ, Zou, M, Lu, L, Lau, D, Ditzel, DA, Delucinge-Vivier, C, Aso, Y, Descombes, P, Bading, H

PLoS Genet 2009
24291638 Regulation of the neuronal transcription factor NPAS4 by REST and microRNAs

Bersten, DC, Wright, JA, McCarthy, PJ, Whitelaw, ML

Biochim Biophys Acta 2014
32327470 Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Opsomer, R, Contino, S, Perrin, F, Gualdani, R, Tasiaux, B, Doyen, P, Vergouts, M, Vrancx, C, Doshina, A, Pierrot, N, Octave, JN, Gailly, P, Stanga, S, Kienlen-Campard, P

eNeuro 2020
31883511 The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

Louis Sam Titus, ASC, Sharma, D, Kim, MS, D'Mello, SR

BMC Neurosci 2019
23020797 Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter

Furukawa-Hibi, Y, Yun, J, Nagai, T, Yamada, K

J Neurochem 2012
33772088 Npas4 impairs fear memory via phosphorylated HDAC5 induced by CGRP administration in mice

Hashikawa-Hobara, N, Mishima, S, Okujima, C, Shitanishi, Y, Hashikawa, N

Sci Rep 2021
28716058 SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model

Lösing, P, Niturad, CE, Harrer, M, Reckendorf, CMZ, Schatz, T, Sinske, D, Lerche, H, Maljevic, S, Knöll, B

Mol Brain 2017
26663079 Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells

Speckmann, T, Sabatini, PV, Nian, C, Smith, RG, Lynn, FC

J Biol Chem 2016
25636686 Adult Deletion of SRF Increases Epileptogenesis and Decreases Activity-Induced Gene Expression

Kuzniewska, B, Nader, K, Dabrowski, M, Kaczmarek, L, Kalita, K

Mol Neurobiol 2016
24050401 Tet1 is critical for neuronal activity-regulated gene expression and memory extinction

Rudenko, A, Dawlaty, MM, Seo, J, Cheng, AW, Meng, J, Le, T, Faull, KF, Jaenisch, R, Tsai, LH

Neuron 2013
26052046 Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes

Madabhushi, R, Gao, F, Pfenning, AR, Pan, L, Yamakawa, S, Seo, J, Rueda, R, Phan, TX, Yamakawa, H, Pao, PC, Stott, RT, Gjoneska, E, Nott, A, Cho, S, Kellis, M, Tsai, LH

Cell 2015
33411316 Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis

Lv, H, Li, Y, Cheng, Q, Chen, J, Chen, W

Mol Neurobiol 2021
19083991 Dynamic regulation of bHLH-PAS-type transcription factor NXF gene expression and neurotrophin dependent induction of the transcriptional control activity

Ooe, N, Kobayashi, K, Motonaga, K, Saito, K, Kaneko, H

Biochem Biophys Res Commun 2009
28232238 Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory

Webb, WM, Sanchez, RG, Perez, G, Butler, AA, Hauser, RM, Rich, MC, O'Bierne, AL, Jarome, TJ, Lubin, FD

Neurobiol Learn Mem 2017
28957664 HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors

Taniguchi, M, Carreira, MB, Cooper, YA, Bobadilla, AC, Heinsbroek, JA, Koike, N, Larson, EB, Balmuth, EA, Hughes, BW, Penrod, RD, Kumar, J, Smith, LN, Guzman, D, Takahashi, JS, Kim, TK, Kalivas, PW, Self, DW, Lin, Y, Cowan, CW

Neuron 2017
24552706 Impaired extinction of learned contextual fear memory in early growth response 1 knockout mice

Han, S, Hong, S, Mo, J, Lee, D, Choi, E, Choi, JS, Sun, W, Lee, HW, Kim, H

Mol Cells 2014
34822816 Inhibition of histone deacetylase 5 ameliorates abnormalities in 16p11.2 duplication mouse model

Rein, B, Conrow-Graham, M, Frazier, A, Cao, Q, Yan, Z

Neuropharmacology 2022
31930559 Interference of neuronal activity-mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

Förstner, P, Knöll, B

FASEB J 2020
34389673 RyR-mediated Ca2+ release elicited by neuronal activity induces nuclear Ca2+ signals, CREB phosphorylation, and Npas4/RyR2 expression

Lobos, P, Córdova, A, Vega-Vásquez, I, Ramírez, OA, Adasme, T, Toledo, J, Cerda, M, Härtel, S, Paula-Lima, A, Hidalgo, C

Proc Natl Acad Sci U S A 2021
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Authored
Orlic-Milacic, M  (2022-04-08)
Reviewed
Lin, Y  (2022-07-29)
Created
Orlic-Milacic, M  (2022-03-14)
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