1. Chromosomes and Gene Expression
  2. Neuroscience

Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

  1. Jürgen Tuvikene  Is a corresponding author
  2. Eli-Eelika Esvald
  3. Annika Rähni
  4. Kaie Uustalu
  5. Anna Zhuravskaya
  6. Annela Avarlaid
  7. Eugene V Makeyev
  8. Tõnis Timmusk  Is a corresponding author
  1. Tallinn University of Technology, Estonia
  2. Kings College London, United Kingdom
https://doi.org/10.7554/eLife.65161
Share this article
Cite this article
  1. Jürgen Tuvikene
  2. Eli-Eelika Esvald
  3. Annika Rähni
  4. Kaie Uustalu
  5. Anna Zhuravskaya
  6. Annela Avarlaid
  7. Eugene V Makeyev
  8. Tõnis Timmusk
(2021)
Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons
eLife 10:e65161.
https://doi.org/10.7554/eLife.65161
  2. Download BibTeX
  3. Download .RIS

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.

The following previously published data sets were used

Article and author information

Author details

  1. Jürgen Tuvikene

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    For correspondence
    jurgen.tuvikene@taltech.ee
    Competing interests
    The authors declare that no competing interests exist.

  2. Eli-Eelika Esvald

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.

  3. Annika Rähni

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2826-4636

  4. Kaie Uustalu

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.

  5. Anna Zhuravskaya

    MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Annela Avarlaid

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.

  7. Eugene V Makeyev

    MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Tõnis Timmusk

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    For correspondence
    tonis.timmusk@taltech.ee
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1015-3348

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.

Metrics

  • 2,888
    views
  • 390
    downloads
  • 26
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jürgen Tuvikene
  2. Eli-Eelika Esvald
  3. Annika Rähni
  4. Kaie Uustalu
  5. Anna Zhuravskaya
  6. Annela Avarlaid
  7. Eugene V Makeyev
  8. Tõnis Timmusk
(2021)
Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons
eLife 10:e65161.
https://doi.org/10.7554/eLife.65161

Share this article

https://doi.org/10.7554/eLife.65161

Categories and tags

Research organisms

Further reading

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

    Kira A Cozzolino, Lynn Sanford ... Dylan J Taatjes
    Research Article

    Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

    1. Chromosomes and Gene Expression

    Cryogenic Electron Microscopy: MagIC beads for scarce macromolecules

    Carlos Moreno-Yruela, Beat Fierz
    Insight

    Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

    1. Chromosomes and Gene Expression

    Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

    Carmina Lichauco, Eric J Foss ... Antonio Bedalov
    Research Article

    The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.