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 $\mathrm{p} 300$ is a type of histone acetyl transfer-

Short answer

Answer: In hypoxic conditions, the transcriptional activator HIF is stabilized and accumulates in the nucleus. HIF interacts with and recruits p300, a histone acetyl transferase (HAT), to the enhancer region of the EPO gene. p300 acetylates nearby histone proteins, causing an open chromatin conformation around the enhancer region of the EPO gene. This facilitates the binding of HIF and other transcription factors to the EPO enhancer, promoting the recruitment of RNA polymerase and enhancer-promoter looping, ultimately leading to transcription of the EPO gene in response to hypoxia.

Step-by-step solution

Understand the roles of HIF, p300, and EPO

First, we need to remind ourselves the roles of each component mentioned. HIF is a transcriptional activator, EPO is a hormone that stimulates red blood cell production in response to hypoxia, and p300 is a type of histone acetyl transferase (HAT). In this model, we have to consider the role of HAT in gene transcription.

Function of histone acetyl transferases (HATs) in gene transcription

Histone acetyl transferases (HATs) are enzymes that acetylate lysine residues on histone proteins. This process neutralizes the positive charge of lysine, reducing the affinity of histones for DNA. Consequently, histones wrap less tightly around DNA, allowing the chromatin to adopt a more open conformation. This open conformation permits the binding of transcription factors and RNA polymerase, leading to gene transcription.

Interactions between HIF, p300, and EPO

According to Wang et al. (2010), HIF recruits p300 to an enhancer for the EPO gene during hypoxia. The deletion of p300 significantly impaired transcription of EPO in response to hypoxia, indicating that p300 plays an essential role in this process.

Propose the model

Based on the provided information, we can propose the following model: 1. Under hypoxic conditions, the transcriptional activator HIF is stabilized and accumulates in the nucleus. 2. HIF interacts with and recruits p300, a histone acetyl transferase (HAT), to the enhancer region of the EPO gene. 3. p300 acetylates nearby histone proteins, resulting in a more open chromatin conformation around the enhancer region of the EPO gene. 4. The open chromatin conformation facilitates the binding of HIF and other transcription factors to the EPO enhancer. 5. This complex formation promotes the recruitment of RNA polymerase and enhancer-promoter looping, ultimately leading to transcription of the EPO gene in response to hypoxia. This model explains how HIF and p300 cooperate to stimulate EPO gene transcription during hypoxia based on their functions as a transcriptional activator and a histone acetyl transferase, respectively.