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

  • 2,858
    views
  • 386
    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. Cell Biology
    2. Chromosomes and Gene Expression

    TPR is required for cytoplasmic chromatin fragment formation during senescence

    Bethany M Bartlett, Yatendra Kumar ... Wendy A Bickmore
    Research Article Updated

    During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.

    1. Chromosomes and Gene Expression
    2. Evolutionary Biology

    The emergence and evolution of gene expression in genome regions replete with regulatory motifs

    Timothy Fuqua, Yiqiao Sun, Andreas Wagner
    Research Article

    Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of regulatory DNA, and also create new regulatory DNA, a process called regulatory emergence. Non-regulatory and regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires a stretch of DNA called a promoter, which contains two motifs called –10 and –35 boxes. However, these motifs may occur in both promoters and non-promoter DNA in multiple copies. They have been implicated in some studies to improve promoter activity, and in others to repress it. Here, we ask whether the presence of such motifs in different genetic sequences influences promoter evolution and emergence. To understand whether and how promoter motifs influence promoter emergence and evolution, we start from 50 ‘promoter islands’, DNA sequences enriched with –10 and –35 boxes. We mutagenize these starting ‘parent’ sequences, and measure gene expression driven by 240,000 of the resulting mutants. We find that the probability that mutations create an active promoter varies more than 200-fold, and is not correlated with the number of promoter motifs. For parent sequences without promoter activity, mutations created over 1500 new –10 and –35 boxes at unique positions in the library, but only ~0.3% of these resulted in de-novo promoter activity. Only ~13% of all –10 and –35 boxes contribute to de-novo promoter activity. For parent sequences with promoter activity, mutations created new –10 and –35 boxes in 11 specific positions that partially overlap with preexisting ones to modulate expression. We also find that –10 and –35 boxes do not repress promoter activity. Overall, our work demonstrates how promoter motifs influence promoter emergence and evolution. It has implications for predicting and understanding regulatory evolution, de novo genes, and phenotypic evolution.

    1. Chromosomes and Gene Expression
    2. Developmental Biology

    N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation

    Valentin Babosha, Natalia Klimenko ... Oksana Maksimenko
    Research Article

    The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila XY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of the MSL complex and are critical for the specific recruitment of the complex to the high-affinity ‘entry’ sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3–7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GS binds to promoters such as MSL1WT but does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.