Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions
Abstract
Studies of gene expression abnormalities in psychiatric or neurological disorders often involve the use of postmortem brain tissue. Compared with single-cell organisms or clonal cell lines, the biological environment and medical history of human subjects cannot be controlled, and are often difficult to document fully. The chance of finding significant and replicable changes depends on the nature and magnitude of the observed variations among the studied subjects. During an analysis of gene expression changes in mood disorders, we observed a remarkable degree of natural variation among 120 samples, which represented three brain regions in 40 subjects. Most of such diversity can be accounted for by two distinct expression patterns, which in turn are strongly correlated with tissue pH. Individuals who suffered prolonged agonal states, such as with respiratory arrest, multi-organ failure or coma, tended to have lower pH in the brain; whereas those who experienced brief deaths, associated with accidents, cardiac events or asphyxia, generally had normal pH. The lower pH samples exhibited a systematic decrease in expression of genes involved in energy metabolism and proteolytic activities, and a consistent increase of genes encoding stress-response proteins and transcription factors. This functional specificity of changed genes suggests that the difference is not merely due to random RNA degradation in low pH samples; rather it reflects a broad and actively coordinated biological response in living cells. These findings shed light on critical molecular mechanisms that are engaged during different forms of terminal stress, and may suggest clinical targets of protection or restoration.
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Very few transcriptomic studies provide information on acute premortem variables or cause of death, which may potentially have a much larger effect on RNA quality and gene expression.
“Additionally, very few transcriptomic studies provide information on acute premortem variables or cause of death, which are particularly important as they may potentially have a much larger effect on RNA quality and gene expression71–76,78–80.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [73]
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- Authors
- Li, J. Z., Vawter, M. P., Walsh, D. M., Tomita, H., Evans, S. J., Choudary, P. V., Lopez, J. F., Avelar, A., Shokoohi, V., Chung, T., Mesarwi, O., Jones, E. G., Watson, S. J., Akil, H., Bunney, W. E., & Myers, R. M.
- Affiliations
- Stanford Medicine (US)
- University of California, Irvine (US)
- University of Michigan (US)
- Stanford University (US)
- University of California, Davis (US)
- Corresponding author
- Li, Jun Z.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-01-20
- Volume
- 13
- Issue
- 6
- Pages
- 609-616
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2113083842
- Cited by
- 261
- References
- 45
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 16 · 2023: 11 · 2022: 6 · 2021: 10 · 2020: 2 · 2019: 4 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 6 · 2014: 9 · 2013: 16 · 2012: 13
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH-60398, P50MH060398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Molecular Biology Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- tissue pH, agonal state, mood disorders, energy metabolism genes, proteolysis, stress proteins, transcription factors, RNA degradation, brain death, asphyxia, coma, multiple organ failure
- MeSH terms
- Adult, Aged, Brain, Cysteine Endopeptidases, Energy Metabolism, Female, Humans, Hydrogen-Ion Concentration, Male, Middle Aged, Multienzyme Complexes, Gene Expression, Mood Disorders, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Proteasome Endopeptidase Complex
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