A locus control region (LCR) is a long-range cis-regulatory element that enhances expression of linked genes at distal chromatin sites. It functions in a copy number-dependent manner and is tissue-specific, as seen in the selective expression of β-globin genes in erythroid cells.^[1] Expression levels of genes can be modified by the LCR and gene-proximal elements, such as promoters, enhancers, and silencers. The LCR functions by recruiting chromatin-modifying, coactivator, and transcription complexes.^[2] Its sequence is conserved in many vertebrates, and conservation of specific sites may suggest importance in function.^[2] It has been compared to a super-enhancer as both perform long-range cis regulation via recruitment of the transcription complex.^[3]

History

The β-globin LCR was identified over 20 years ago in studies of transgenic mice. These studies determined that the LCR was required for normal regulation of beta-globin gene expression.^[4] Evidence of the presence of this additional regulatory element came from a group of patients that lacked a 20 kb region upstream of the β-globin cluster that was vital for expression of any of the β-globin genes. Even though all of the genes themselves and the other regulatory elements were intact, without this domain, none of the genes in the β-globin cluster were expressed.^[5]

Examples

Although the name implies that the LCR is limited to a single region, this implication only applies to the β-globin LCR (HBB-LCR). Other studies have found that a single LCR can be distributed in multiple areas around and inside the genes it controls. The β-globin LCR in mice and humans is found 6–22 kb upstream of the first globin gene (epsilon). It controls the following genes:^[1][2]

• HBE1, hemoglobin subunit epsilon (embryonic)
• HBG2, hemoglobin subunit gamma-2 (fetal)
• HBG1, hemoglobin subunit gamma-1 (fetal)
• HBD, hemoglobin subunit delta (adult)
• HBB, hemoglobin subunit beta (adult)

There is an opsin LCR (OPSIN-LCR) controlling the expression of OPN1LW and the first copies of OPN1MW on the human X chromosome, upstream of these genes.^[6] A dysfunctional LCR can cause loss of expression of both opsins, leading to blue cone monochromacy.^[7] This LCR is also conserved in teleost fishes including zebrafish.^[8]

As of 2002, there are 21 LCR areas known in human.^[1] As of 2019, 11 human LCRs are recorded in the NCBI database.^[9]

Proposed models of LCR function

Although studies have been conducted to attempt to identify a model of how the LCR functions, evidence for the following models is not strongly supported or precluded.^[1]

Looping model

Transcription factors bind to hypersensitive site cores and cause the LCR to form a loop that can interact with the promoter of the gene it regulates.^[1]

Tracking model

Transcription factors bind to the LCR to form a complex. The complex moves along the DNA helix until it can bind to the promoter of the gene it regulates. Once bound, the transcriptional apparatus increases gene expression.^[1]

Facilitated tracking model

This hypothesis combines the looping and tracking models, suggesting that the transcription factors bind to the LCR to form a loop, which then seeks and binds to the promoter of the gene it regulates.^[1]

Linking model

Transcription factors bind to DNA from the LCR to the promoter in an orderly fashion using non-DNA-binding proteins and chromatin modifiers. This changes chromatin conformation to expose the transcriptional domain.^[1]

Diseases related to the LCR

Studies in transgenic mice have shown that deletion of the β-globin LCR causes the region of chromosome to condense into a heterochromatic state.^[1][2] This leads to decreased expression of β-globin genes, which can cause β-thalassemia in humans and mice.