Question

When challenged with a low oxygen environment, known as hypoxia, the body produces a hormone called erythropoietin (EPO), which then stimulates red blood cell production to carry more oxygen. Transcription of the gene encoding EPO is dependent upon the hypoxia-inducible factor (HIF), which is a transcriptional activator. However, HIF alone is not sufficient to activate EPO. For example, Wang et al. (2010. PLOS ONE 5: e10002) showed that HIF recruits another protein called p300 to an enhancer for the EPO gene. Furthermore, deletion of p300 significantly impaired transcription of the EPO gene in response to hypoxia. Given that p300 is a type of histone acetyl transferase, how might p300 influence transcription of the EPO gene?

Accepted Answer

Understand the role of p300 as a histone acetyl transferase (HAT), which means it adds acetyl groups to histone proteins around DNA. Recall that acetylation of histones by HATs like p300 generally reduces the positive charge on histones, decreasing their affinity for negatively charged DNA, leading to a more relaxed chromatin structure. Recognize that a relaxed or open chromatin structure allows transcription factors and the transcriptional machinery better access to the DNA, facilitating gene transcription. Connect that p300, recruited by HIF to the EPO gene enhancer, likely acetylates histones in that region, promoting chromatin remodeling and enhancing transcriptional activation of the EPO gene. Conclude that without p300's histone acetylation activity, the chromatin remains more condensed, hindering transcription factor access and thus impairing EPO gene transcription in response to hypoxia.

Key Concepts

Hypoxia-Inducible Factor (HIF)

Role of p300 as a Histone Acetyltransferase

Transcriptional Co-activation and Enhancer Function