Abstract
Transcription factors (TFs) orchestrate gene expression programs crucial for brain function, but we lack detailed information about TF binding in human brain tissue. We generated a multiomic resource (ChIP–seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several postmortem brain regions, including binding maps for more than 100 TFs. We demonstrate improved measurements of TF activity, including motif recognition and gene expression modeling, upon identification and removal of high TF occupancy regions. Further, predictive TF binding models demonstrate a bias for these high-occupancy sites. Neuronal TFs SATB2 and TBR1 bind unique regions depleted for such sites and promote neuronal gene expression. Binding sites for TFs, including TBR1 and PKNOX1, are enriched for risk variants associated with neuropsychiatric disorders, predominantly in neurons. This work, titled BrainTF, is a powerful resource for future studies seeking to understand the roles of specific TFs in regulating gene expression in the human brain.
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Data availability
All relevant data generated by this study have been made publicly available through the PsychENCODE Consortium and are available for download at the following link: https://doi.org/10.7303/syn51942384.1. This includes the raw sequencing data (fastq) and processed results that can be used for analyses or visualizations, including bed files of peak calls and bigwigs of signal tracks.
Code availability
The analysis scripts used to generate the images and statistical output in this paper are available on GitHub (https://github.com/aanderson54/Loupe_BrainTF). These scripts use openly accessible packages within the R (v.4.2.2) environment. The associated ‘read.me’ file also provides detailed instructions regarding how to use the provided code.
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Acknowledgements
We thank the brain donors and their families, without whom this research would not have been possible. This study was supported by National Institutes of Health grant 5R01MH110472 awarded to R.M.M. and G.M.C., the Memory and Mobility Fund from HudsonAlpha Institute for Biotechnology and support from the Pritzker Neuropsychiatric Research Consortium. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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R.M.M., G.M.C. and J.M.L. conceptualized the study. J.M.L., L.F.R., I.R.-N., K.T.-L. and R.J. performed the investigation. J.M.L., L.F.R. and A.G.A. curated the data. J.M.L., A.G.A., B.M. and I.R.-N. performed the formal analysis. W.E.B., B.G.B., P.C., A.S., S.J.W. and H.A. provided brain tissue and resources. J.M.L. wrote the original draft of the manuscript. R.M.M. and G.M.C. acquired funding.
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Supplementary information
Supplementary Information
Supplementary Figs. 1–14.
Supplementary Table 1
Postmortem metadata.
Supplementary Table 2
Experiment list and quality control.
Supplementary Table 3
Antibodies for ChIP–seq.
Supplementary Table 4
ChIP–seq peak unions.
Supplementary Table 5
GREAT pathways enrichment.
Supplementary Table 6
HOT skewness values.
Supplementary Table 7
motifmatchR results.
Supplementary Table 8
Motif calling MEME.
Supplementary Table 9
Virtual ChIP–seq.
Supplementary Table 10
Partitioned heritability.
Supplementary Table 11
Statistics.
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Loupe, J.M., Anderson, A.G., Rizzardi, L.F. et al. Multiomic profiling of transcription factor binding and function in human brain. Nat Neurosci 27, 1387–1399 (2024). https://doi.org/10.1038/s41593-024-01658-8
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DOI: https://doi.org/10.1038/s41593-024-01658-8
