Temporal analysis of enhancers during mouse cerebellar development reveals dynamic and novel regulatory functions

Abstract

We have identified active enhancers in the mouse cerebellum at embryonic and postnatal stages which provides a view of novel enhancers active during cerebellar development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Furthermore, by comparing our data with relevant brain development ENCODE histone profiles and cerebellar single-cell datasets we have been able to generalize and expand on the presented analyses, respectively. We have made the results of our analyses available online in the Developing Mouse Cerebellum Enhancer Atlas (https://goldowitzlab.shinyapps.io/developing_mouse_cerebellum_enhancer_atlas/), where our dataset can be efficiently queried, curated and exported by the scientific community to facilitate future research efforts. Our study provides a valuable resource for studying the dynamics of gene expression regulation by enhancers in the developing cerebellum and delivers a rich dataset of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.

Data availability

Sequencing data have been deposited in GEO under accession code: GSE183697

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Miguel Ramirez

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Yuliya Badayeva

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Joanna Yeung

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0551-5305
  4. Joshua Wu

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Ayasha Abdalla-Wyse

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Erin Yang

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5629-2362
  7. FANTOM 5 Consortium

    Department of Molecular Genetics, Hospital for Sick Children, Toronto, Canada
  8. Brett Trost

    The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4863-7273
  9. Stephen W Scherer

    Department of Molecular Genetics, Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8326-1999
  10. Daniel Goldowitz

    Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, Canada
    For correspondence
    dang@cmmt.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4756-4017

Funding

NSERC Discovery Award

  • Daniel Goldowitz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All studies were conducted according to the protocols approved by the Institutional Animal Care and Use Committee and the Canadian Council on Animal Care at the University of British Columbia.

Copyright

© 2022, Ramirez 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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  1. Miguel Ramirez
  2. Yuliya Badayeva
  3. Joanna Yeung
  4. Joshua Wu
  5. Ayasha Abdalla-Wyse
  6. Erin Yang
  7. FANTOM 5 Consortium
  8. Brett Trost
  9. Stephen W Scherer
  10. Daniel Goldowitz
(2022)
Temporal analysis of enhancers during mouse cerebellar development reveals dynamic and novel regulatory functions
eLife 11:e74207.
https://doi.org/10.7554/eLife.74207

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https://doi.org/10.7554/eLife.74207

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