5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: Differential regulation of variant transcripts by early-life events

James (Jim) McCormick, V. Lyons, M. D. Jacobson, J. Noble, J. Diorio, M. Nyirenda, S. Weaver, W. Ester, J. L W Yau, M. J. Meaney, J. R. Seckl, K. E. Chapman

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

Glucocorticoid receptor (GR) gene expression is regulated in a complex tissue-specific manner, notably by early-life environmental events that program tissue GR levels. We have identified and characterized several new rat GR mRNAs. All encode a common protein, but differ in their 5′-leader sequences as a consequence of alternate splicing of, potentially, 11 different exon 1 sequences. Most are located in a 3-kb CpG island, upstream of exon 2, that exhibits substantial promoter activity in transfected cells. Ribonuclease (RNase) protection analysis demonstrated significant levels of six alternate exons 1 in vivo in rat, with differences between liver, hippocampus, and thymus reflecting tissue-specific differences in promoter activity. Two of the alternate exons 1 (exons 16 and 110) were expressed in all tissues examined, together present in 77-87% of total GR mRNA. The remaining GR transcripts contained tissue-specific alternate first exons. Importantly, tissue-specific first exon usage was altered by perinatal environmental manipulations. Postnatal handling, which permanently increases GR in the hippocampus, causing attenuation of stress responses, selectively elevated GR mRNA containing the hippocampus-specific exon 17. Prenatal glucocorticoid exposure, which increases hepatic GR expression and produces adult hyperglycemia, decreased the proportion of hepatic GR mRNA containing the predominant exon 110, suggesting an increase in a minor exon 1 variant. Such tissue specificity of promoter usage allows differential GR regulation and programming.

Original languageEnglish (US)
Pages (from-to)506-517
Number of pages12
JournalMolecular Endocrinology
Volume14
Issue number4
DOIs
StatePublished - 2000
Externally publishedYes

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Glucocorticoid Receptors
Exons
Messenger RNA
Hippocampus
Liver
Organ Specificity
CpG Islands
Alternative Splicing
Ribonucleases
Hyperglycemia
Thymus Gland
Glucocorticoids
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific : Differential regulation of variant transcripts by early-life events. / McCormick, James (Jim); Lyons, V.; Jacobson, M. D.; Noble, J.; Diorio, J.; Nyirenda, M.; Weaver, S.; Ester, W.; Yau, J. L W; Meaney, M. J.; Seckl, J. R.; Chapman, K. E.

In: Molecular Endocrinology, Vol. 14, No. 4, 2000, p. 506-517.

Research output: Contribution to journalArticle

McCormick, JJ, Lyons, V, Jacobson, MD, Noble, J, Diorio, J, Nyirenda, M, Weaver, S, Ester, W, Yau, JLW, Meaney, MJ, Seckl, JR & Chapman, KE 2000, '5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: Differential regulation of variant transcripts by early-life events', Molecular Endocrinology, vol. 14, no. 4, pp. 506-517. https://doi.org/10.1210/me.14.4.506
McCormick, James (Jim) ; Lyons, V. ; Jacobson, M. D. ; Noble, J. ; Diorio, J. ; Nyirenda, M. ; Weaver, S. ; Ester, W. ; Yau, J. L W ; Meaney, M. J. ; Seckl, J. R. ; Chapman, K. E. / 5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific : Differential regulation of variant transcripts by early-life events. In: Molecular Endocrinology. 2000 ; Vol. 14, No. 4. pp. 506-517.
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