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.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, California 94305, USA.
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
authors.forename: David M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tomita
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Evans
authors.forename: Prabhakara V
authors.initials: PV
authors.lastname: Choudary
authors.forename: Juan F
authors.initials: JF
authors.lastname: Lopez
authors.forename: Abigail
authors.initials: A
authors.lastname: Avelar
authors.forename: Vida
authors.initials: V
authors.lastname: Shokoohi
authors.forename: Tisha
authors.initials: T
authors.lastname: Chung
authors.forename: Omar
authors.initials: O
authors.lastname: Mesarwi
authors.forename: Edward G
authors.initials: EG
authors.lastname: Jones
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex