Abstract
Recent studies of nuclear organization have shown an apparent correlation between the localization of genes within the interphase nucleus and their transcriptional status. In several instances, actively transcribed gene loci have been found significantly looped away from their respective chromosome territories (CTs), presumably as a result of their expression. Here, we show evidence that extrusion of a gene locus from a CT by itself is not necessarily indicative of transcriptional activity, but also can reflect a poised state for activation. We found the murine and a wild-type human β-globin locus looped away from their CTs at a high frequency only in a proerythroblast cell background, prior to the activation of globin transcription. Conversely, a mutant allele lacking the locus control region (LCR), which is required for high-level globin expression, was mostly coincident with the CT. The LCR may thus be responsible for the localization of the globin locus prior to activation. Replacement of the LCR with a B-cell-specific regulatory element, while also extruding the globin locus, brought it closer to the repressive centromeric heterochromatin compartment. We therefore suggest that the looping of gene loci from their CTs may reflect poised and repressed states, as well as the previously documented transcriptionally active state.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bender MA, Bulger M, Close J, Groudine M (2000) β-Gobin gene switching and DNase I sensitivity of the endogenous b-gobin locus in mice do not require the locus control region. Mol Cell 5: 387-393.
Brown KE, Amoils S, Horn JM et al. (2001) Expression of alpha-and beta-globin genes occurs within different nuclear domains in haemopoietic cells. Natl Cell Biol 3: 602-606.
Cremer T, Cremer C (2001) Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Gen 2: 292-301.
Cremer T, Kurz A, Zirbel R et al. (1993) Role of chromosome territories in the functional compartmentalization of the cell nucleus. Cold Spring Harb Symp Quant Biol 58: 777-792.
Dolznig H, Bartunek P, Nasmyth K, Mullner EW, Beug H (1995) Terminal differentiation of normal chicken erythroid progenitors: shortening of G1 correlates with loss of D-cyclin/cdk4 expression and altered cell size control. Cell Growth Differ 6: 1341-1352.
Epner E, Reik A, Cimobora D et al. (1998) The β-gobin LCR is not necessary for an open chromatin structure or developmentally regulated transcription of the native mouse β-gobin locus. Mol Cell 2: 447-455.
Francastel C, Poindessous-Jazat V, Augery-Bourget Y, Robert-Lezenes J (1997) NF-E2p18/mafK is required in DMSO-induced differentiation of Friend erythroleukemia cells by enhancing NF-E2 activity. Leukemia 11: 273-280.
Francastel C, Walters MC, Groudine M, Martin DI (1999) A functional enhancer suppresses silencing of a transgene and prevents its localization close to centrometric heterochromatin. Cell 99: 259-269.
Francastel C, Magis W, Groudine M(2001) Nuclear relocation of a transactivator subunit precedes target gene activation. Proc Natl Acad Sci USA 98: 12120-12125.
Friend C, Scher W, Holland JG, Sato T (1971) Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. Proc Natl Acad Sci USA 68: 378-382.
Kosak ST, Skok JA, Medina KL et al. (2002) Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296: 158-162.
Kurz A, Lamel S, Nickolenko JE et al. (1996). Active and inactive genes localize preferentially in the periphery of chromosome territories. J Cell Biol 135: 1195-1205.
Madisen L, Groudine M (1994). Identication of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells. Genes Dev 8: 2212-2226.
Mahairas GG, Wallace JC, Smith K et al. 1999. Sequencetagged connectors: a sequence approach to mapping and scanning the human genome. Proc Natl Acad Sci USA 96: 9739-9744.
Mahy NL, Perry PE, Bickmore, WA (2002) Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J Cell Biol 159: 753-763.
Reik A, Telling A, Zitnik G, Cimbora D, Epner E, Groudine M (1998) The locus control region is necessary for gene expression in the human beta-globin locus but not the maintenance of an open chromatin structure in erythroid cells. Mol Cell Biol 18: 5992-6000.
Sabbattini P, Lundgren M, Georgiou A, Chow C, Warnes G, Dillon N (2001) Binding of Ikaros to the lambda5 promoter silences transcription through a mechanism that does not require heterochromatin formation. Embo J 20: 2812-2822.
Sawado S, Igarashi K, Groudine M (2001) Activation of the β-major globin gene transcription is associated with recruitment of NF-E2 to the β-globin LCR and gene promoter. Proc Natl Acad Sci USA 98: 10226-10231.
Schübeler D, Francastel C, Cimbora DM, Reik A, Martin DI, Groudine M (2000) Nuclear localization and histone 524 T. Ragoczy et al. acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. Genes Dev 14: 940-950.
Verschure PJ, van Der Kraan I, Manders EM, van Driel R (1999) Spatial relationship between transcription sites and chromosome territories. J Cell Biol 147: 13-24.
Visser AE, Françoise F, Fakan S, Aten JA (2000) High resolution analysis of interphase chromosome domains. J Cell Sci 113: 2585-2593.
Volpi EV, Chevret, E, Jones T et al. (2000) Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. J Cell Sci 113 (Pt 9): 1565-1576.
Williams RR, Broad S, Sheer D, Ragoussis J (2002) Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei. Exp Cell Res 272: 163-175.
Zirbel RM, Mathieu UR, Kurz A, Cremer T, Lichter P (1993) Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries. Chromosome Res 1: 93-106.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ragoczy, T., Telling, A., Sawado, T. et al. A genetic analysis of chromosome territory looping: diverse roles for distal regulatory elements. Chromosome Res 11, 513–525 (2003). https://doi.org/10.1023/A:1024939130361
Issue Date:
DOI: https://doi.org/10.1023/A:1024939130361