Biology: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.[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]
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.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Locus control regions". Blood 100 (9): 3077–86. November 2002. doi:10.1182/blood-2002-04-1104. PMID 12384402.
- ↑ 2.0 2.1 2.2 2.3 "The human beta-globin locus control region". European Journal of Biochemistry 269 (6): 1589–99. March 2002. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
- ↑ "Phase Separation and Transcription Regulation: Are Super-Enhancers and Locus Control Regions Primary Sites of Transcription Complex Assembly?". BioEssays 41 (1): e1800164. January 2019. doi:10.1002/bies.201800164. PMID 30500078.
- ↑ "What is a gene, post-ENCODE? History and updated definition". Genome Research 17 (6): 669–81. June 2007. doi:10.1101/gr.6339607. PMID 17567988.
- ↑ Nussbaum, Robert; McInnes, Roderick; Willard, Huntington (2016). Thompson &Thompson Genetics in Medicine (Eighth ed.). Philadelphia: Elsevier. pp. 200.
- ↑ "Genetics of variation in human color vision and the retinal cone mosaic". Current Opinion in Genetics & Development 16 (3): 301–7. June 2006. doi:10.1016/j.gde.2006.04.002. PMID 16647849.
- ↑ "Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic". Vision Research 50 (19): 1989–99. September 2010. doi:10.1016/j.visres.2010.07.009. PMID 20638402.
- ↑ "Regulatory function of conserved sequences upstream of the long-wave sensitive opsin genes in teleost fishes". Vision Research 51 (21–22): 2295–303. November 2011. doi:10.1016/j.visres.2011.09.010. PMID 21971525.
- ↑ "Search: "locus control region"[title AND "Homo sapiens"[porgn] AND alive[prop]"]. https://www.ncbi.nlm.nih.gov/gene/?term=%22locus+control+region%22%5Btitle%5D+AND+%22Homo+sapiens%22%5Bporgn%5D+AND+alive%5Bprop%5D.
 |  |
