Generating specificity and diversity in the transcriptional response to hypoxia

• Published in: Nature reviews. Genetics Vol. 10; no. 12; pp. 821 - 832
• Main Authors: Lendahl, Urban, Lee, Kian Leong, Yang, Henry, Poellinger, Lorenz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiovascular disease; Cell Hypoxia; Cellular signal transduction; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene Function; Genetic aspects; Genomes; Homeostasis; Human Genetics; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Metabolism; Molecular and cellular biology; Molecular genetics; Neoplasms - metabolism; Oxygen - metabolism; Phosphorylation; Physiology; Proteins; review-article; Transcription factors; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Singapore; Gene silencing; Oxygen; Specificity; Transcription; Micro RNA; Transcriptome; Epigenetics; Hypoxia; Review
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg2665

Key Points Hypoxia and the cellular hypoxic response have key roles in homeostasis and physiological adaptations, as well as in pathophysiological conditions. The cellular hypoxic response can generate both diversity and specificity in the downstream signalling output, despite a relatively simple core signalling pathway. Hypoxia-inducible factor-α proteins constitute key transcriptional regulators in the cellular hypoxic response, and are subject to various different post-translational modifications. Analysis of the hypoxia transcriptional response has begun to reveal a core hypoxic transcriptional signature in addition to cell type-specific gene activation events. The transcriptional responses to acute and chronic hypoxia are distinct. Likewise, hypoxia-mimicking chemical compounds have a substantially broader transcriptional output than hypoxia. Intersections with other signalling mechanisms, such as Myc and Notch signalling, contribute to modulation of the hypoxic response. In addition to the core hypoxic transcriptional pathway, several mechanisms exist to allow transcriptional diversity and specificity. This Review highlights recent advances in our understanding of the mechanisms and factors that contribute to the tailoring of the appropriate hypoxic transcriptional response. The sensing of oxygen levels and maintenance of oxygen homeostasis is crucial for cells. The hypoxic-sensitive regulation of gene expression allows information about the oxygen status to be converted into appropriate cellular responses. Although there is a core transcriptional pathway, the signalling cascade can be modified to allow diversity and specificity in the transcriptional output. In this Review, we discuss recent advances in our understanding of the mechanisms and factors that contribute to the observed diversity and specificity. A deeper knowledge about how hypoxic signalling is tuned will further our understanding of the cellular hypoxic response in normal physiology and how it becomes derailed in disease.