Locus Control Regions (LCRs)

Abstract

Locus control regions (LCRs) are defined as deoxyribonucleic acid sequence elements that confer high‐level, tissue‐specific expression to stably integrated transgenes in a position‐independent manner. As such, LCRs mediate gene activation and render a high proportion of genomic integration sites permissive for such expression, and are distinguished from transcriptional enhancers, which like LCRs are capable of mediating gene activation over large genomic distances. The mechanistic basis for the functional distinction between LCRs and enhancers is unclear. LCRs appear to subsume the separate functions of both transcriptional enhancers and chromatin insulators, but may be qualitatively different from either of these classes of regulatory elements. At their native loci, however, LCRs may only be required for a subset of the activities that they display in transgenic contexts.

Key Concepts:

  • LCRs are cis‐acting DNA regulatory elements that have been identified at a number of tissue‐specific gene loci in vertebrates.

  • LCRs are defined by their activity in transgenic assays, where in addition to activating transcription of linked transgenes, they are capable of rendering most integration sites permissive for expression.

  • The mechanistic basis for LCR function in transgenes is unknown, and there is evidence both for LCRs representing simply a very strong enhancer and for LCRs harbouring an activity entirely distinct from that of enhancers, involving the long‐range propagation of an ‘open’ chromatin structure.

  • At the endogenous loci from which LCRs have been derived, they appear to be required for a variety of different functions, not all of which correspond to their activity in transgenes.

  • LCR function has been correlated with the regulation of nuclear localisation of linked genes.

Keywords: transcription; chromatin; enhancer; promoter; gene regulation

Figure 1.

Expression in mice of transgenes containing different regulatory elements. A hypothetical transgene is integrated at random genomic sites in mice linked to only its promoter (a), the promoter and a classical enhancer (b), or the promoter and a locus control region (LCR; (c)). The sorts of expression patterns that might be expected among different mice, each containing the transgene in a different integration site, in each case are shown: the darker the shading the higher the level of expression; no shading indicates no expression.

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References

Aronow BJ, Ebert CA, Valerius MT et al. (1995) Dissecting a locus control region: facilitation of enhancer function by extended enhancer‐flanking sequences. Molecular and Cellular Biology 15: 1123–1135.

Bender MA, Bulger M, Close J and Groudine M (2000) Beta‐globin gene switching and DNase I sensitivity of the endogenous beta‐globin locus in mice do not require the locus control region. Molecular Cell 5: 387–393.

Bender MA, Ragoczy T, Lee J et al. (2012) The hypersensitive sites of the murine β‐globin locus control region act independently to affect nuclear localization and transcriptional elongation. Blood 119: 3820–3827.

Bulger M and Groudine M (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144: 327–339.

Ellis J, Talbot D, Dillon N and Grosveld F (1993) Synthetic human beta‐globin 5′HS2 constructs function as locus control regions only in multicopy transgene concatamers. EMBO Journal 12: 127–134.

Fernandez LA, Winkler M and Grosschedl R (2001) Matrix attachment region‐dependent function of the immunoglobulin mu enhancer involves histone acetylation at a distance without changes in enhancer occupancy. Molecular and Cellular Biology 21: 196–208.

Forrester WC, Takegawa S, Papayannopoulou T, Stamatoyannopoulos G and Groudine M (1987) Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin‐expressing hybrids. Nucleic Acids Research 15: 10159–10177.

Forrester WC, Thompson C, Elder JT and Groudine M (1986) A developmentally stable chromatin structure in the human beta‐globin gene cluster. Proceedings of the National Academy of Sciences of the USA 83: 1359–1363.

Forrester WC, van Genderen C, Jenuwein T and Grosschedl R (1994) Dependence of enhancer‐mediated transcription of the immunoglobulin mu gene on nuclear matrix attachment regions. Science 265: 1221–1225.

Grosveld F, van Assendelft GB, Greaves DR and Kollias G (1987) Position‐independent, high‐level expression of the human beta‐globin gene in transgenic mice. Cell 51: 975–985.

Hardison R, Slightom JL, Gumucio DL et al. (1997) Locus control regions of mammalian beta‐globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights. Gene 205: 73–94.

de Laat W, Klous P, Kooren J et al. (2008) Three‐dimensional organization of gene expression in erythroid cells. Current Topics in Developmental Biology 82: 117–139.

McMorrow T, van den Wijngaard A, Wollenschlaeger A et al. (2000) Activation of the beta‐globin locus by transcription factors and chromatin modifiers. EMBO Journal 19: 4986–4996.

Miele A and Dekker J (2008) Long‐range chromosomal interactions and gene regulation. Molecular BioSystems 4: 1046–1056.

Noordermeer D, Branco MR, Splinter E et al. (2008) Transcription and chromatin organization of a housekeeping gene cluster containing an integrated beta‐globin locus control region. PLoS Genetics 4: e1000016.

Ragoczy T, Bender MA, Telling A et al. (2006) The locus control region is required for association of the murine beta‐globin locus with engaged transcription factories during erythroid maturation. Genes & Development 20: 1447–1457.

Ragoczy T, Telling A, Sawado T et al. (2003) A genetic analysis of chromosome territory looping: diverse roles for distal regulatory elements. Chromosome Research 11: 513–525.

Ronai D, Berru M and Shulman MJ (1999) Variegated expression of the endogenous immunoglobulin heavy‐chain gene in the absence of the intronic locus control region. Molecular and Cellular Biology 19: 7031–7040.

Schubeler D, Groudine M and Bender MA (2001) The murine beta‐globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes. Proceedings of the National Academy of Sciences of the USA 98: 11432–11437.

Further Reading

Barkness G and West A (2012) Chromatin insulator elements: establishing barriers to set heterochromatin boundaries. Epigenomics 4: 67–80.

Buecker C and Wysocka J (2012) Enhancers as information integration hubs in development: lessons from genomics. Trends in Genetics 28: 276–284.

Dean A (2006) On a chromosome far, far away: LCRs and gene expression. Trends in Genetics 22: 38–45.

Ellis J, Tan‐Un KC, Harper A et al. (1996) A dominant chromatin‐opening activity in 5′ hypersensitive site 3 of the human beta‐globin locus control region. EMBO Journal 15: 562–568.

Festenstein R, Sharghi‐Namini S, Fox M et al. (1999) Heterochromatin protein 1 modifies mammalian PEV in a dose‐ and chromosomal‐context‐dependent manner. Nature Genetics 23: 457–461.

Festenstein R, Tolaini M, Corbella P et al. (1996) Locus control region function and heterochromatin‐induced position effect variegation. Science 271: 1123–1125.

Jenuwein T, Forrester WC, Fernandez‐Herrero LA et al. (1997) Extension of chromatin accessibility by nuclear matrix attachment regions. Nature 385: 269–272.

Li Q, Harju S and Peterson KR (1999) Locus control regions: coming of age at a decade plus. Trends in Genetics 15: 403–408.

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How to Cite close
Bulger, Michael, and Groudine, Mark(Jun 2013) Locus Control Regions (LCRs). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005034.pub2]