Biological Sciences Division
Published November 23, 2022 | Version v1
Journal article Open

Top2a promotes the development of social behavior via PRC2 and H3K27me3

Creators

  • 1. University of Utah
  • 2. University of Chicago
  • 3. Harvard University
  • 4. MDI Biological Laboratory

Description

Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The raw and processed RNA-seq data have been deposited in the GEO under accession number GSE181730 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE181730). Code is available on the GitHub repository (https://github.com/yijie-geng/Fishbook) and is archived on Zenodo under DOI 10.5281/zenodo.5171582.

Files

sciadv.abm7069.pdf

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Additional details

Identifiers

DOI
10.1126/sciadv.abm7069
Other
oai:uchicago.tind.io:11017

Funding

NIEHS
K99ES031050

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Biophysical Sciences