Locus Control Region

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. 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. Its sequence is conserved in many vertebrates, and conservation of specific sites may suggest importance in function. It has been compared to a super-enhancer as both perform long-range ''cis'' regulation via recruitment of the transcription complex.

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. 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.

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:

* 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. A dysfunctional LCR can cause loss of expression of both opsins, leading to blue cone monochromacy. This LCR is also conserved in teleost fishes including zebrafish.

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

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.

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.

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.

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.

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.

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. This leads to decreased expression of β-globin genes, which can cause β-thalassemia in humans and mice.

References

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Epigenetics