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
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]

  • 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. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G (November 2002). "Locus control regions". Blood. 100 (9): 3077–86. doi:10.1182/blood-2002-04-1104. PMC 2811695. PMID 12384402.
  2. Levings PP, Bungert J (March 2002). "The human beta-globin locus control region". European Journal of Biochemistry. 269 (6): 1589–99. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
  3. Gurumurthy A, Shen Y, Gunn EM, Bungert J (January 2019). "Phase Separation and Transcription Regulation: Are Super-Enhancers and Locus Control Regions Primary Sites of Transcription Complex Assembly?". BioEssays. 41 (1): e1800164. doi:10.1002/bies.201800164. PMC 6484441. PMID 30500078.
  4. Gerstein MB, Bruce C, Rozowsky JS, Zheng D, Du J, Korbel JO, et al. (June 2007). "What is a gene, post-ENCODE? History and updated definition". Genome Research. 17 (6): 669–81. doi:10.1101/gr.6339607. PMID 17567988.
  5. Nussbaum R, McInnes R, Willard H (2016). Thompson &Thompson Genetics in Medicine (Eighth ed.). Philadelphia: Elsevier. p. 200.
  6. Deeb SS (June 2006). "Genetics of variation in human color vision and the retinal cone mosaic". Current Opinion in Genetics & Development. 16 (3): 301–7. doi:10.1016/j.gde.2006.04.002. PMID 16647849.
  7. Carroll J, Rossi EA, Porter J, Neitz J, Roorda A, Williams DR, Neitz M (September 2010). "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. doi:10.1016/j.visres.2010.07.009. PMC 3005209. PMID 20638402.
  8. Tam KJ, Watson CT, Massah S, Kolybaba AM, Breden F, Prefontaine GG, Beischlag TV (November 2011). "Regulatory function of conserved sequences upstream of the long-wave sensitive opsin genes in teleost fishes". Vision Research. 51 (21–22): 2295–303. doi:10.1016/j.visres.2011.09.010. PMID 21971525.
  9. "Search: "locus control region"[title] AND "Homo sapiens"[porgn] AND alive[prop]". NCBI Gene. Retrieved 20 August 2019.
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