Identification ofcis-Elements and Transcription Factors Regulating Neuronal Activity-Dependent Transcription of HumanBDNFGene

Abstract

Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodent BDNF neuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of human BDNF (hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNF gene or transfected with hBDNF promoter constructs, respectively. We identified an asymmetric E-box-like element, PasRE [basic helix-loop-helix (bHLH)-PAS transcription factor response element], in hBDNF promoter I and demonstrate that binding of this element by bHLH-PAS transcription factors ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) and NPAS4 (neuronal PAS domain protein 4) is crucial for neuronal activity-dependent transcription from promoter I. We show that binding of CREB (cAMP response element-binding protein) to the cAMP/Ca(2+)-response element (CRE) in hBDNF promoter IV is critical for activity-dependent transcription from this promoter and that upstream stimulatory factor (USF) transcription factors also contribute to the activation by binding to the upstream stimulatory factor binding element (UBE) in hBDNF promoter IV. However, we report that full induction of hBDNF exon IV mRNA transcription is dependent on ARNT2 and NPAS4 binding to a PasRE in promoter IV. Finally, we demonstrate that CRE and PasRE elements in hBDNF promoter IX are required for the induction of this promoter by neuronal activity. Together, the results of this study have identified the cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

“…Because, as mentioned above, Npas4 can regulate the expression of Bdnf exon IV, our data suggest that chronic duloxetine may restore the correct expression of Bdnf in SERT À/À rats via modulation of the transcription factor. Moreover, we show that the expression of Arnt2, another transcription factor that cooperate with Npas4 in the regulation of Bdnf exon IV (Pruunsild et al, 2011) is also significantly reduced in SERT À/À rats, although its expression can be restored by duloxetine treatment in the prefrontal cortex, but not in the hippocampus.…”

“…It is interesting to note that Npas4 is a transcription factor associated with promoters I and IV of the Bdnf gene (Pruunsild et al, 2011), suggesting that it may directly regulate activity-dependent expression of the neurotrophin . Interestingly, we have previously demonstrated that SERT À/À rats have reduced Bdnf expression in the hippocampus and prefrontal cortex, and that this occurs through the modulation of different Bdnf transcripts, including exon I and exon IV .…”

“…To further the analysis of the transcription factors that may contribute to the Bdnf changes present in SERT À/À rats, we investigated the expression of Arnt2, a member of the Arnt family, that specifically cooperate with Npas4 in the transcriptional control of Bdnf exons (Ooe et al, 2009;Pruunsild et al, 2011). In the hippocampus, we found a significant genotype effect (F 1,24 ¼ 13.696, po0.01) as demonstrated by the reduction of Arnt2 mRNA levels in SERT À/À rats (À37%, po0.05; two-way ANOVA with SCPHT), although duloxetine treatment was not able to modulate the Arnt2 expression in wild-type, as well as in SERT À/À rats (Figure 3b).…”

“…The Bdnf gene has a very complex structure that gives rise to multiple transcripts, which are regulated through the cooperation and interaction of different transcription factors (Aid et al, 2007;Greer and Greenberg, 2008;Pruunsild et al, 2011). Among them is the neuronal PAS domain protein 4 (Npas4), which specifically controls the activity-dependent Bdnf mRNA levels by acting on promoters I and IV.…”

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…Previous studies have shown how the interaction between all these factors is complex and likely involves BDNF, the demethylating protein GADD45B, and hypoxia-related mechanisms. For example, binding of CREB 51 and GADD45B 52 in the BDNF region upstream of the rs6265 SNP has been detected. Moreover, BHLHB2 and GADD45B are regulated by hypoxia, since they have a highstringency HIF1 binding site, 53,54 and BHLHB2 represses expression of MITF, 53 a TF stimulating HIF1a expression.…”