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Long-range Regulation of How Genes are Turned “Off” and “On”

Two studies have advanced our understanding of the transcriptional regulation of a set of red blood cell genes call globin genes, and of how these genes are turned on and off. Transcription is a biologic process that involves the transcribing or copying of genetic information from DNA into RNA. Immature red blood cells produce globin proteins, key components of hemoglobin, which carry oxygen in red blood cells from the lungs to the rest of the body. Production of globin proteins is a highly regulated process to ensure that these genes are turned on (“expressed”) or off at appropriate times during the development of red blood cells from their precursors in the bone marrow.

The mammalian β-globin gene locus was among the first gene clusters to provide insight into how gene regulation is influenced by long-range chromosomal interactions between DNA sequences far from and near to the protein-coding segment of a gene. Specifically, these interactions occur between a powerful element called an enhancer that helps turn on the β-globin gene, also referred to as the gene’s locus control region (LCR), and a DNA element called a promoter, which is immediately adjacent to the gene and helps regulate whether it is on or off. Scientists continue to study enhancers such as the LCR in order to more fully understand their role in the regulation of gene expression generally.

In the first study, scientists devised a strategy to delineate whether loops of chromosomal DNA, created by the interaction between the β-globin gene promoter and LCR, are a cause or an effect of gene transcription. Using erythroid precursor cells (cells that develop into normal red blood cells) to study the β-globin gene locus transcription process, researchers showed for the first time that the protein Ldb1 is a key looping factor involved in long-range regulation of gene transcription. Furthermore, their experimental manipulations that forced or impaired the creation of the DNA loop which allows the LCR to interact with the β-globin gene confirmed that loop formation plays an important role in initiating β-globin gene transcription and is not simply a consequence of the gene being “turned on.”

In the second study, investigators sought to determine the relative contribution of four segments of the LCR to its function in regulating β-globin gene transcription and also to determine the location of the β-globin locus within the cell’s nucleus. Nuclear location influences whether or not a gene is expressed. Scientists refer to these LCR segments as DNase I hypersensitive sites (HSs) because they are regions of the enhancer that are extremely sensitive to breakdown into smaller pieces (digestion) by the enzyme DNase I. Sensitivity to DNase I is a measure of the transcriptional status of a gene and indicates that this region of DNA is “open” or exposed, so that factors that promote transcription can bind to it. Mice were engineered that had various combinations of HSs deleted, and the effects of these deletions on gene transcription were measured in relationship to the position of the β-globin gene locus in the nucleus. The results showed that while the effects of the HSs are additive, only two were needed for the β-globin locus to be repositioned towards the center of the nucleus where gene transcription can become active. However, all four of the HSs of the LCR were shown to be needed for β-globin transcription to be completed efficiently.

These studies add considerable knowledge to our understanding of the regulation of gene transcription. Identification of looping factors such as Ldb1 and delineation of the various components required for proper β-globin transcription may help the development of new ways to treat hematologic diseases, such as sickle cell disease, by reactivating dormant hemoglobin genes.