Tissue‐specific Locus Control: Structure and Function


All developmental processes involve decisions in which the developmental fate of precursor cells is restricted to a single lineage by establishing a unique gene expression pattern. The activation at each of these gene loci involves restructuring chromatin as a necessary prerequisite for the assembly of the transcription apparatus. Tissue‐specific locus activation is controlled by the interplay between sequence‐specific transcription factors, chromatin‐modifying activities and basic chromatin components.

Keywords: gene locus activation; transcriptional control elements; histones; nucleosomes; chromatin; position effect; globin

Figure 1.

Organization of the human β‐globin cluster on chromosome 11 (top) and the human α‐globin cluster on chromosome 16 (bottom). Functional genes are indicated as boxes. DNAaseI hypersensitive sites that mark the positions of cis‐regulatory elements such as promoters (P) or enhancers (E) are indicated as vertical arrows. The top and bottom diagrams depict the chromosomal organization of globin and nonglobin genes.



Agalioti T, Lomvardas S, Parekh B et al. (2000) Ordered recruitment of chromatin modifying and general transcription factors to the IFN‐beta promoter. Cell 103: 667–678.

Anguita E, Hughes J, Heyworth C et al. (2004) Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA‐1 and GATA‐2. EMBO Journal 23: 2841–2852.

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

Bulger M, Bender MA, van Doorninck JH et al. (2000) Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse β‐globin gene clusters. Proceedings of the National Academy of Sciences of the USA 97: 14560–14565.

Craddock CF, Vyas P, Sharpe JA et al. (1995) Contrasting effects of alpha and beta globin regulatory elements on chromatin structure may be related to their different chromosomal environments. EMBO Journal 14: 1718–1726.

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

Forsberg EC and Bresnick EH (2001) Histone acetylation beyond promoters: long‐range acetylation patterns in the chromatin world. BioEssays 23: 820–830.

Gross DS and Garrard WT (1988) Nuclease hypersensitive sites in chromatin. Annual Review of Biochemistry 57: 159–197.

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

Hanscombe O, Whyatt D, Fraser P et al. (1991) Importance of globin gene order for correct developmental expression. Genes and Development 5: 1387–1394.

Holbert MA and Marmorstein R (2005) Structure and activity of enzymes that remove histone modifications. Current Opinion Structural Biology 15: 673–680.

Jenuwein T and Allis CD (2001) Translating the histone code. Science 293: 1074–1080.

Krysinska H, Hoogenkamp M, Ingram R et al. (2007) A two‐step, PU.1 dependent, mechanism for developmentally regulated chromatin remodelling and transcription of the c‐fms gene. Molecular Cellular Biology 27: 878–887.

Laherty CD, Yang WM, Sun JM et al. (1997) Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89: 349–356.

Li B, Carey M and Workman JL (2007) The role of chromatin during transcription. Cell 128: 707–719.

Margueron R, Trojer P and Reinberg D (2005) The key to development: interpreting the histone code. Current Opinion in Genetics and Development 45: 463–476.

Merika M and Thanos D (2001) Enhanceosomes. Current Opinion in Genetics and Development 11: 205–208.

Mellor J (2006) Dynamic nucleosomes and gene transcription. Trends in Genetics 22: 320–329.

Narlikar GJ, Fan HY and Kingston RE (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108: 475–487.

Schübeler D, Francastel C, Cimbora DM et al. (2000) Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human β‐globin locus. Genes and Development 14: 940–950.

Sharpe JA, Wells DJ, Whitelaw E et al. (1993) Analysis of the human α‐globin gene cluster in transgenic mice. Proceedings of the National Academy of Sciences of the USA 90: 11262–11266.

Thoma F (1992) Nucleosome positioning. Biochimica et Biophysica Acta 1130: 1–19.

Wallace HA, Marques‐Kranc F, Richardson M et al. (2007) Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence. Cell 128: 197–209.

Further Reading

Bonifer C (2000) Developmental regulation of eukaryotic gene loci: which cis‐regulatory information is required? Trends in Genetics 16: 310–315.

Brown KE, Amoils S, Horn JM et al. (2001) Expression of α‐ and β‐globin genes occurs within different nuclear domains in haemopoietic cells. Nature Cell Biology 3: 602–606.

Engel JD and Tanimoto K (2000) Looping, linking and chromatin activity: new insights into β‐globin locus regulation. Cell 100: 499–502.

Flint J, Tufarelli C, Peden J et al. (2001) Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster. Human Molecular Genetics 10: 371–382.

Fry CJ and Peterson L (2001) Chromatin remodelling enzymes: who's on first? Current Biology 11: R185–R197.

Gribnau J, Diderich K, Pruzina S, Calzolari R and Fraser P (2000) Intergenic transcription and developmental remodeling of chromatin subdomains in the human β‐globin locus. Molecular Cell 5: 377–386.

Higgs DR (1998) Do LCRs open chromatin domains? Cell 95: 299–302.

Higgs DR, Sharpe JA and Wood WG (1998) Understanding alpha globin gene expression: a step towards effective gene therapy. Seminars in Hematology 35: 93–104.

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bonifer, Constanze(Sep 2007) Tissue‐specific Locus Control: Structure and Function. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005292.pub2]