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Developmental regulation of human cortex transcription and its clinical relevance at single base resolution
Open accessAbstract
Transcriptome analysis of human brain provides fundamental insight into development and disease, but it largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and in the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders such as schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data show conserved molecular signatures of transcriptional dynamics across brain development, have potential clinical relevance and highlight the incomplete annotation of the human brain transcriptome.
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“Transcriptomic analyses suggest that genes associated with psychiatric disorders are highly expressed during development 5,6 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [6]
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“We highlight two primate-specific lncRNAs, LINC00693 and LINC00689. Both interact with miRNA processing complexes and are typically downregulated during development12, but are upregulated in ASD cortex (Fig. 1c, d, Extended Data Fig. 2n).”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [12]
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“Lines above the plot indicate pairwise significance with a one-sided Wilcoxon rank-sum test between brain and the other tissues.”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [12]
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Metadata
- Authors
- Jaffe, A. E., Shin, J., Collado-Torres, L., Leek, J. T., Tao, R., Li, C., Gao, Y., Jia, Y., Maher, B. J., Hyde, T. M., Kleinman, J. E., & Weinberger, D. R.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Jaffe, Andrew E
- Weinberger, Daniel R
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-12-15
- Volume
- 18
- Issue
- 1
- Pages
- 154-161
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4281298
- OpenAlex
- W2002097805
- Cited by
- 156
- References
- 63
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 5 · 2021: 4 · 2020: 20 · 2019: 19 · 2018: 18 · 2017: 20 · 2016: 27 · 2015: 13
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R03MH096539, R21MH102791)
- National Institute of General Medical Sciences (R01GM105705)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- human prefrontal cortex, brain development, brain aging, transcriptome annotation, neurodevelopmental disorders, schizophrenia, mouse cortex, neuronal differentiation, neuronal maturation
- MeSH terms
- Aging, Animals, Cerebral Cortex, Chromatin, Female, Fetus, Humans, Infant, Infant, Newborn, Neurons, Pregnancy, Conserved Sequence, Gene Expression Regulation, Developmental, Mice, Transcriptome
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