Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons
- Tallinn University of Technology, Estonia
- Kings College London, United Kingdom
Abstract
Brain-derived neurotrophic factor (BDNF) controls the survival, growth, and function of neurons both during the development and in the adult nervous system. Bdnf is transcribed from several distinct promoters generating transcripts with alternative 5' exons. Bdnf transcripts initiated at the first cluster of exons have been associated with the regulation of body weight and various aspects of social behavior, but the mechanisms driving the expression of these transcripts have remained poorly understood. Here, we identify an evolutionarily conserved intronic enhancer region inside the Bdnf gene that regulates both basal and stimulus-dependent expression of the Bdnf transcripts starting from the first cluster of 5' exons in mouse and rat neurons. We further uncover a functional E-box element in the enhancer region, linking the expression of Bdnf and various pro-neural basic helix-loop-helix transcription factors. Collectively, our results shed new light on the cell-type- and stimulus-specific regulation of the important neurotrophic factor BDNF.
Data availability
Mass-spectrometry results of the in vitro DNA pulldown experiment are provided in Supplementary Table 3.
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Widespread transcription at neuronal activity-regulated enhancersNCBI Gene Expression Omnibus, GSE21161.
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Rapid and Pervasive Changes in Genome-Wide Enhancer Usage During Mammalian DevelopmentNCBI Gene Expression Omnibus, GSE52386.
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Genome-wide identification and characterization of functional neuronal activity-dependent enhancersNCBI Gene Expression Omnibus, GSE60192.
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NeuroD2 ChIP-SEQ from embryonic cortexNCBI Gene Expression Omnibus, GSE67539.
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A protein interaction network of mental disorder factors in neural stem cellsNCBI Gene Expression Omnibus, GSE70872.
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Genome-wide maps of EGR1 binding in mouse frontal cortexNCBI Gene Expression Omnibus, GSE67482.
Article and author information
Author details
Funding
Estonian Research Council (IUT19-18)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Annika Rähni
- Kaie Uustalu
- Annela Avarlaid
- Tõnis Timmusk
Estonian Research Council (PRG805)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Annela Avarlaid
- Tõnis Timmusk
Norwegian Financial Mechanism (EMP128)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Annika Rähni
- Kaie Uustalu
- Tõnis Timmusk
European Regional Development Fund (2014-2020.4.01.15-0012)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Annika Rähni
- Kaie Uustalu
- Annela Avarlaid
- Tõnis Timmusk
H2020-MSCA-RISE-2016 (EU734791)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Anna Zhuravskaya
- Annela Avarlaid
- Eugene V Makeyev
- Tõnis Timmusk
Biotechnology and Biological Sciences Research Council (BB/M001199/1)
- Anna Zhuravskaya
- Eugene V Makeyev
Biotechnology and Biological Sciences Research Council (BB/M007103/1)
- Anna Zhuravskaya
- Eugene V Makeyev
Biotechnology and Biological Sciences Research Council (BB/R001049/1)
- Anna Zhuravskaya
- Eugene V Makeyev
European Regional Development Fund (ASTRA 2014-2020.4.01.16-0032)
- Jürgen Tuvikene
- Eli-Eelika Esvald
- Annela Avarlaid
- Tõnis Timmusk
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Tuvikene et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons
eLife 10:e65161.
https://doi.org/10.7554/eLife.65161
Further reading
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- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
The mRNA 5'-cap structure removal by the decapping enzyme DCP2 is a critical step in gene regulation. While DCP2 is the catalytic subunit in the decapping complex, its activity is strongly enhanced by multiple factors, particularly DCP1, which is the major activator in yeast. However, the precise role of DCP1 in metazoans has yet to be fully elucidated. Moreover, in humans, the specific biological functions of the two DCP1 paralogs, DCP1a and DCP1b, remain largely unknown. To investigate the role of human DCP1, we generated cell lines that were deficient in DCP1a, DCP1b, or both to evaluate the importance of DCP1 in the decapping machinery. Our results highlight the importance of human DCP1 in decapping process and show that the EVH1 domain of DCP1 enhances the mRNA-binding affinity of DCP2. Transcriptome and metabolome analyses outline the distinct functions of DCP1a and DCP1b in human cells, regulating specific endogenous mRNA targets and biological processes. Overall, our findings provide insights into the molecular mechanism of human DCP1 in mRNA decapping and shed light on the distinct functions of its paralogs.
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- Chromosomes and Gene Expression
- Computational and Systems Biology
Genes are often regulated by multiple enhancers. It is poorly understood how the individual enhancer activities are combined to control promoter activity. Anecdotal evidence has shown that enhancers can combine sub-additively, additively, synergistically, or redundantly. However, it is not clear which of these modes are more frequent in mammalian genomes. Here, we systematically tested how pairs of enhancers activate promoters using a three-way combinatorial reporter assay in mouse embryonic stem cells. By assaying about 69,000 enhancer-enhancer-promoter combinations we found that enhancer pairs generally combine near-additively. This behaviour was conserved across seven developmental promoters tested. Surprisingly, these promoters scale the enhancer signals in a non-linear manner that depends on promoter strength. A housekeeping promoter showed an overall different response to enhancer pairs, and a smaller dynamic range. Thus, our data indicate that enhancers mostly act additively, but promoters transform their collective effect non-linearly.
