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]
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]
See also: Human β-globin locus.
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]
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]
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]
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]
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]
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]
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]
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.