Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues
Open accessAbstract
Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy ≈4,000 promoter sites in vivo , depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.
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The reduced abundance of two well-characterized CREB targets TrkB and cFos provides further confirmation that CREB-mediated transcription is reduced in rTg4510 mice.
“The reduced abundance of two well-characterized CREB targets TrkB and cFos (52,53) provide further confirmation that CREBmediated transcription is reduced in rTg4510 mice (Supple- mentary Material, Fig. S3).”
From CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy (2012) · cites this paper as [53]
The citation is attached to the description of TrkB and cFos as CREB targets; the reduction in rTg4510 mice is attributed to the citing paper’s supplementary figure. The Results and Promoter passages discuss CREB target genes generally, but searches for TrkB, cFos, and FOS found no passage identifying either named gene as a target. (LLM, conf=0.72)
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- Authors
- Zhang, X., Odom, D. T., Koo, S.-H., Conkright, M. D., Canettieri, G., Best, J., Chen, H., Jenner, R., Herbolsheimer, E., Jacobsen, E., Kadam, S., Ecker, J. R., Emerson, B., Hogenesch, J. B., Unterman, T., Young, R. A., & Montminy, M.
- Affiliations
- Genomics Institute of the Novartis Research Foundation (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-03-07
- Volume
- 102
- Issue
- 12
- Pages
- 4459-4464
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC555478
- OpenAlex
- W2106726734
- Cited by
- 992
- References
- 4
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 34 · 2023: 46 · 2022: 41 · 2021: 47 · 2020: 32 · 2019: 31 · 2018: 45 · 2017: 50 · 2016: 47 · 2015: 44 · 2014: 53 · 2013: 49 · 2012: 58
- FWCI
- 24.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM037828, GM R01-037828)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068655)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- CREB, CREB phosphorylation, cAMP signaling, CREB-binding protein, transcriptional coactivator, promoter binding, cAMP response element, DNA methylation, tissue-specific gene regulation, protein kinase A
- MeSH terms
- Cyclic AMP, Base Sequence, Binding Sites, Cell Line, DNA, Gene Expression Regulation, Humans, Islets of Langerhans, Phosphorylation, Promoter Regions, Genetic, Tissue Distribution, Transcription Factors, Transcriptional Activation, Genome, Human, Cyclic AMP Response Element-Binding Protein, DNA Methylation, Hepatocytes
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