Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions

Jun Z. Li, Marquis P. Vawter, David M. Walsh, Hiroaki Tomita, Simon J. Evans, Prabhakara V Choudary, Juan F. Lopez, Abigail Avelar, Vida Shokoohi, Tisha Chung, Omar Mesarwi, Edward G. Jones, Stanley J. Watson, Huda Akil, William E. Bunney, Richard M. Myers

Research output: Contribution to journalArticle

197 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)609-616
Number of pages8
JournalHuman Molecular Genetics
Volume13
Issue number6
DOIs
StatePublished - Mar 15 2004

Fingerprint

Gene Expression
Brain
Asphyxia
RNA Stability
Coma
Heat-Shock Proteins
Nervous System Diseases
Mood Disorders
Energy Metabolism
Genes
Accidents
Psychiatry
Transcription Factors
Cell Line

ASJC Scopus subject areas

  • Genetics

Cite this

Li, J. Z., Vawter, M. P., Walsh, D. M., Tomita, H., Evans, S. J., Choudary, P. V., ... Myers, R. M. (2004). Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Human Molecular Genetics, 13(6), 609-616. https://doi.org/10.1093/hmg/ddh065

Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. / Li, Jun Z.; Vawter, Marquis P.; Walsh, David M.; Tomita, Hiroaki; Evans, Simon J.; Choudary, Prabhakara V; Lopez, Juan F.; Avelar, Abigail; Shokoohi, Vida; Chung, Tisha; Mesarwi, Omar; Jones, Edward G.; Watson, Stanley J.; Akil, Huda; Bunney, William E.; Myers, Richard M.

In: Human Molecular Genetics, Vol. 13, No. 6, 15.03.2004, p. 609-616.

Research output: Contribution to journalArticle

Li, JZ, Vawter, MP, Walsh, DM, Tomita, H, Evans, SJ, Choudary, PV, Lopez, JF, Avelar, A, Shokoohi, V, Chung, T, Mesarwi, O, Jones, EG, Watson, SJ, Akil, H, Bunney, WE & Myers, RM 2004, 'Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions', Human Molecular Genetics, vol. 13, no. 6, pp. 609-616. https://doi.org/10.1093/hmg/ddh065
Li, Jun Z. ; Vawter, Marquis P. ; Walsh, David M. ; Tomita, Hiroaki ; Evans, Simon J. ; Choudary, Prabhakara V ; Lopez, Juan F. ; Avelar, Abigail ; Shokoohi, Vida ; Chung, Tisha ; Mesarwi, Omar ; Jones, Edward G. ; Watson, Stanley J. ; Akil, Huda ; Bunney, William E. ; Myers, Richard M. / Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 6. pp. 609-616.
@article{94c7a8a49a9043bdad123f53c4a62ae4,
title = "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.",
author = "Li, {Jun Z.} and Vawter, {Marquis P.} and Walsh, {David M.} and Hiroaki Tomita and Evans, {Simon J.} and Choudary, {Prabhakara V} and Lopez, {Juan F.} and Abigail Avelar and Vida Shokoohi and Tisha Chung and Omar Mesarwi and Jones, {Edward G.} and Watson, {Stanley J.} and Huda Akil and Bunney, {William E.} and Myers, {Richard M.}",
year = "2004",
month = "3",
day = "15",
doi = "10.1093/hmg/ddh065",
language = "English (US)",
volume = "13",
pages = "609--616",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions

AU - Li, Jun Z.

AU - Vawter, Marquis P.

AU - Walsh, David M.

AU - Tomita, Hiroaki

AU - Evans, Simon J.

AU - Choudary, Prabhakara V

AU - Lopez, Juan F.

AU - Avelar, Abigail

AU - Shokoohi, Vida

AU - Chung, Tisha

AU - Mesarwi, Omar

AU - Jones, Edward G.

AU - Watson, Stanley J.

AU - Akil, Huda

AU - Bunney, William E.

AU - Myers, Richard M.

PY - 2004/3/15

Y1 - 2004/3/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=12144287672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12144287672&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddh065

DO - 10.1093/hmg/ddh065

M3 - Article

VL - 13

SP - 609

EP - 616

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 6

ER -