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.
Sequencing data have been deposited in GEO under accession code: GSE183697
Temporal analysis of enhancers during mouse brain development reveals dynamic regulatory function and identifies novel regulators of cerebellar development.NCBI Gene Expression Omnibus, GSE183697.
Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellumNCBI Gene Expression Omnibus, GSE60731.
The Atoh1 targetome in murine postnatal cerebellumNCBI Gene Expression Omnibus, GSE22111.
A Single-Cell Transcriptional Atlas of the Developing Murine CerebellumEuropean Nucleotide Archive.
Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cellsDeveloping mouse cerebellum snATAC-seq atlas.
- Daniel Goldowitz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Genevieve Konopka, University of Texas Southwestern Medical Center, United States
© 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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