Locus control region

The 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]

History

The 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.[3] 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.[4]

Location

Although the name implies that the LCR is limited to a single region, this implication only applies to the β-globin 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).[1][2]

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.

References

  1. 1 2 3 4 5 6 7 8 Li Q, Peterson KR, Fang X, Stamatoyannopoulos G (November 2002). "Locus control regions". Blood 100 (9): 3077–3086. doi:10.1182/blood-2002-04-1104. PMC 2811695. PMID 12384402.
  2. 1 2 3 4 Levings PP, Bungert J (March 2002). "The human β-globin locus control region". European Journal of Biochemistry 269 (6): 1589–1599. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
  3. ↑ Gerstein MB, Bruce C, Rozowsky JS, et al. (June 2007). "What is a gene, post-ENCODE? History and updated definition". Genome Res. 17 (6): 669–681. doi:10.1101/gr.6339607. PMID 17567988.
  4. ↑ Nussbaum, Robert; McInnes, Roderick; Willard, Huntington (2016). Thompson &Thompson Genetics in Medicine (Eighth ed.). Philadelphia: Elsevier. p. 200.
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