locus control region


Summary: A regulatory region first identified in the human beta-globin locus but subsequently found in other loci. The region is believed to regulate GENETIC TRANSCRIPTION by opening and remodeling CHROMATIN structure. It may also have enhancer activity.

Top Publications

  1. Li Q, Peterson K, Fang X, Stamatoyannopoulos G. Locus control regions. Blood. 2002;100:3077-86 pubmed
  2. Navas P, Swank R, Yu M, Peterson K, Stamatoyannopoulos G. Mutation of a transcriptional motif of a distant regulatory element reduces the expression of embryonic and fetal globin genes. Hum Mol Genet. 2003;12:2941-8 pubmed
    High-level beta-globin gene expression is dependent on the presence of the locus control region (LCR), a powerful regulatory element physically characterized by five DNase I-hypersensitive sites (HS), designated HS1-HS5...
  3. Harju S, Navas P, Stamatoyannopoulos G, Peterson K. Genome architecture of the human beta-globin locus affects developmental regulation of gene expression. Mol Cell Biol. 2005;25:8765-78 pubmed
    ..When a beta(m)-globin gene was placed between the locus control region (LCR) and the epsilon-globin gene, beta(m)-globin expression dominated primitive and definitive ..
  4. Noordermeer D, Branco M, Splinter E, Klous P, van Ijcken W, Swagemakers S, et al. Transcription and chromatin organization of a housekeeping gene cluster containing an integrated beta-globin locus control region. PLoS Genet. 2008;4:e1000016 pubmed publisher
    ..We identified long-range interactions between the LCR and two upregulated genes and propose that LCR-gene contacts via chromatin looping determine which genes are transcriptionally enhanced. ..
  5. Guglielmi L, Truffinet V, Magnoux E, Cogne M, Denizot Y. The polymorphism of the locus control region lying downstream the human IgH locus is restricted to hs1,2 but not to hs3 and hs4 enhancers. Immunol Lett. 2004;94:77-81 pubmed
  6. Cajiao I, Zhang A, Yoo E, Cooke N, Liebhaber S. Bystander gene activation by a locus control region. EMBO J. 2004;23:3854-63 pubmed
    ..the Igbeta (CD79b) gene is situated between the pituitary-specific human growth hormone (hGH) gene and its locus control region (hGH LCR)...
  7. Lisowski L, Sadelain M. Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in beta-thalassemic mice. Blood. 2007;110:4175-8 pubmed
    ..We show here the major roles played by 2 lesser-known locus control region elements, termed HS1 and HS4...
  8. Gomos Klein J, Harrow F, Alarcón J, Ortiz B. CTCF-independent, but not CTCF-dependent, elements significantly contribute to TCR-alpha locus control region activity. J Immunol. 2007;179:1088-95 pubmed
    The mouse TCRalpha/TCRdelta/Dad1 gene locus bears a locus control region (LCR) that drives high-level, position-independent, thymic transgene expression in chromatin...
  9. Manchado M, Catanese G, Ponce M, Funes V, Infante C. The complete mitochondrial genome of the Senegal sole, Solea senegalensis Kaup. Comparative analysis of tandem repeats in the control region among soles. DNA Seq. 2007;18:169-75 pubmed publisher
    ..senegalensis. Phylogenetic analysis showed that 7 out of 9 of haplotypes bearing three copies grouped in a separate cluster. Possible mechanisms influencing the evolution of control region among soles are discussed...

More Information


  1. Merriwether D, Hodgson J, Friedlaender F, Allaby R, Cerchio S, Koki G, et al. Ancient mitochondrial M haplogroups identified in the Southwest Pacific. Proc Natl Acad Sci U S A. 2005;102:13034-9 pubmed
    ..These haplogroups from Northern Island Melanesia extend the existing schema for macrohaplogroup M, with many independent branches distributed across Asia, East Africa, Australia, and Near Oceania. ..
  2. Hanawa H, Hargrove P, Kepes S, Srivastava D, Nienhuis A, Persons D. Extended beta-globin locus control region elements promote consistent therapeutic expression of a gamma-globin lentiviral vector in murine beta-thalassemia. Blood. 2004;104:2281-90 pubmed
    ..that a gamma-globin lentiviral vector utilizing the beta-globin promoter and elements from the beta-globin locus control region (LCR) totaling 1.7 kb could correct murine beta-thalassemia...
  3. Harrow F, Ortiz B. The TCRalpha locus control region specifies thymic, but not peripheral, patterns of TCRalpha gene expression. J Immunol. 2005;175:6659-67 pubmed
    ..The mouse TCR alpha-chain gene locus contains a cis-acting locus control region (LCR) that has been shown to direct integration site-independent, lymphoid organ-specific expression of ..
  4. Kim S, Bultman S, Jing H, Blobel G, Bresnick E. Dissecting molecular steps in chromatin domain activation during hematopoietic differentiation. Mol Cell Biol. 2007;27:4551-65 pubmed
    ..of the beta-globin locus, in which GATA-1 assembles dispersed complexes at the promoters and the distal locus control region (LCR), revealed molecular intermediates, including GATA-1-independent and GATA-1-containing LCR ..
  5. Pipkin M, Ljutic B, Cruz Guilloty F, Nouzova M, Rao A, Zuniga Pflucker J, et al. Chromosome transfer activates and delineates a locus control region for perforin. Immunity. 2007;26:29-41 pubmed
    ..These cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC ..
  6. Layon M, Ackley C, West R, Lowrey C. Expression of GATA-1 in a non-hematopoietic cell line induces beta-globin locus control region chromatin structure remodeling and an erythroid pattern of gene expression. J Mol Biol. 2007;366:737-44 pubmed
    ..GATA-1 is also necessary for the formation and function of the locus control region DNase I hypersensitive site (HS) core elements...
  7. Ho Y, Elefant F, Liebhaber S, Cooke N. Locus control region transcription plays an active role in long-range gene activation. Mol Cell. 2006;23:365-75 pubmed
    ..How these determinants function remains poorly understood. The hGH gene is activated by a 5'-remote locus control region (LCR)...
  8. Cai S, Lee C, Kohwi Shigematsu T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet. 2006;38:1278-88 pubmed
    ..Thus, SATB1 is a necessary determinant for the hitherto unidentified higher-order, transcriptionally active chromatin structure that forms on T(H)2 cell activation. ..
  9. Gavrilov A, Razin S. Spatial configuration of the chicken alpha-globin gene domain: immature and active chromatin hubs. Nucleic Acids Res. 2008;36:4629-40 pubmed publisher
    ..These incomplete chromatin hubs were present in proliferating cultured erythroblasts which did not express globin genes. In lymphoid cells only the interaction between the alpha(D) promoter and the CpG island was detected...
  10. Routledge S, Proudfoot N. Definition of transcriptional promoters in the human beta globin locus control region. J Mol Biol. 2002;323:601-11 pubmed
    ..the presence of intergenic transcripts throughout the locus, and demonstrated that transcription of the locus control region (LCR) initiates within an ERV9 endogenous retroviral long-terminal repeat (LTR) upstream of DNase I ..
  11. Harrow F, Amuta J, Hutchinson S, Akwaa F, Ortiz B. Factors binding a non-classical Cis-element prevent heterochromatin effects on locus control region activity. J Biol Chem. 2004;279:17842-9 pubmed
    A locus control region (LCR) is a cis-acting gene-regulatory element capable of transferring the expression characteristics of its gene locus of origin to a linked transgene...
  12. Pi W, Yang Z, Wang J, Ruan L, Yu X, Ling J, et al. The LTR enhancer of ERV-9 human endogenous retrovirus is active in oocytes and progenitor cells in transgenic zebrafish and humans. Proc Natl Acad Sci U S A. 2004;101:805-10 pubmed
    ..3,000-4,000 human gene loci including the beta-globin gene locus where the ERV-9 LTR is juxtaposed to the locus control region (beta-LCR) far upstream of the globin genes...
  13. de Graaff L, Argente J, van Meurs J, Uitterlinden A, Hokken Koelega A. Genetic polymorphisms in the locus control region and promoter of GH1 are related to serum IGF-I levels and height in patients with isolated growth hormone deficiency and healthy controls. Horm Res Paediatr. 2010;73:25-34 pubmed publisher
    Expression of the human growth hormone (GH) gene (GH1) is regulated by a locus control region (LCR) and the highly polymorphic GH1 promoter...
  14. Carter D, Chakalova L, Osborne C, Dai Y, Fraser P. Long-range chromatin regulatory interactions in vivo. Nat Genet. 2002;32:623-6 pubmed
    ..We show that the classical enhancer element, HS2 of the prototypical locus control region (LCR) of the beta-globin gene cluster, is in close physical proximity to an actively transcribed HBB (beta-..
  15. Masternak K, Peyraud N, Krawczyk M, Barras E, Reith W. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nat Immunol. 2003;4:132-7 pubmed
    In vivo, a wild-type pattern of major histocompatibility complex (MHC) class II expression requires a locus control region (LCR)...
  16. Zhang S, Qian R. The interaction between the human beta-globin locus control region and nuclear matrix. Cell Res. 2002;12:411-6 pubmed
    ..We suggest that the HS2 core DNA sequence binding to the nuclear matrix in Hu-induced HEL cells may open the structure of chromatin to make the LCR accessible to the promoter of beta-globin gene and to promote its transcription. ..
  17. Johnson K, Grass J, Park C, Im H, Choi K, Bresnick E. Highly restricted localization of RNA polymerase II within a locus control region of a tissue-specific chromatin domain. Mol Cell Biol. 2003;23:6484-93 pubmed
    ..For the murine beta-globin locus, Pol II binds the beta-globin locus control region (LCR) far upstream of the beta-globin promoters, independent of recruitment to and activation of the ..
  18. Lee G, Fields P, Griffin T, Flavell R. Regulation of the Th2 cytokine locus by a locus control region. Immunity. 2003;19:145-53 pubmed
    ..Expression of the IL4 promoter-luciferase reporter was transactivated by GATA-3 irrespective of position in the locus, suggesting the global nature of this regulation. The LCR itself, however, does not respond directly to GATA-3. ..
  19. Jia C, Huang S, Zeng Y. [A study of the effect of locus control region elements HS2 and HS3 on beta-globin gene expression]. Yi Chuan Xue Bao. 2002;29:565-70 pubmed
    HS2 and HS3 are important elements of human beta-globin locus control region (LCR)...
  20. Woon Kim Y, Kim S, Geun Kim C, Kim A. The distinctive roles of erythroid specific activator GATA-1 and NF-E2 in transcription of the human fetal ?-globin genes. Nucleic Acids Res. 2011;39:6944-55 pubmed publisher
    ..This idea is supported by the distinctive binding pattern of CBP and Brg1 in the ?-globin locus. Furthermore GATA-1-dependent loop formation between HS5 and 3'HS1 suggests correlation between histone modifications and chromatin looping. ..
  21. Ho Y, Liebhaber S, Cooke N. The role of the hGH locus control region in somatotrope restriction of hGH-N gene expression. Mol Endocrinol. 2011;25:877-84 pubmed publisher
    ..Recent studies indicate that deoxyribonuclease I hypersensitive site I (HSI) of the hGH locus control region, located at -14...
  22. Song S, Kim A, Ragoczy T, Bender M, Groudine M, Dean A. Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation. Blood. 2010;116:2356-64 pubmed publisher
    ..SCL, GATA-1, and LMO2 form a complex that is required to establish spatial proximity between the ?-globin locus control region and gene and for transcription activation during erythroid differentiation...
  23. Shimotsuma M, Matsuzaki H, Tanabe O, Campbell A, Engel J, Fukamizu A, et al. Linear distance from the locus control region determines epsilon-globin transcriptional activity. Mol Cell Biol. 2007;27:5664-72 pubmed
    ..The human beta-globin locus control region (LCR) activates expression of five genes in erythroid cells, including the proximal embryonic epsilon- and ..
  24. Kim A, Song S, Brand M, Dean A. Nucleosome and transcription activator antagonism at human beta-globin locus control region DNase I hypersensitive sites. Nucleic Acids Res. 2007;35:5831-8 pubmed
    ..We analyzed the chromatin structure of human beta-globin locus control region hypersensitive sites in erythroid cells expressing embryonic and fetal globin genes...
  25. Shimotsuma M, Okamura E, Matsuzaki H, Fukamizu A, Tanimoto K. DNase I hypersensitivity and epsilon-globin transcriptional enhancement are separable in locus control region (LCR) HS1 mutant human beta-globin YAC transgenic mice. J Biol Chem. 2010;285:14495-503 pubmed publisher
    ..genes (epsilon, Ggamma, Agamma, delta, beta) in the human beta-globin locus depends on enhancement by the locus control region, which consists of five DNase I hypersensitive sites (5'HS1 through 5'HS5)...
  26. Kim S, Fields P, Flavell R. Demethylation of a specific hypersensitive site in the Th2 locus control region. Proc Natl Acad Sci U S A. 2007;104:17052-7 pubmed
    ..Here, we characterize demethylation events of the Th2 cytokine locus control region (LCR)...
  27. Palstra R, de Laat W, Grosveld F. Beta-globin regulation and long-range interactions. Adv Genet. 2008;61:107-42 pubmed publisher
    ..The demonstration that the major regulatory element of the beta-globin locus, the locus control region (LCR), is in close proximity to the active beta-globin genes validates the contact model for long-range ..
  28. Fleetwood M, Ho Y, Cooke N, Liebhaber S. DNase I hypersensitive site II of the human growth hormone locus control region mediates an essential and distinct long-range enhancer function. J Biol Chem. 2012;287:25454-65 pubmed publisher
    ..In this "neutral" DNA context, HSII was required for the recruitment of HAT activity. These data establish HSII as a nonredundant component of the hGH LCR essential for establishment of robust levels of hGH-N gene expression. ..
  29. Chan P, Wai A, Philipsen S, Tan Un K. 5'HS5 of the human beta-globin locus control region is dispensable for the formation of the beta-globin active chromatin hub. PLoS ONE. 2008;3:e2134 pubmed publisher
    Hypersensitive site 5 (5'HS5) of the beta-globin Locus Control Region functions as a developmental stage-specific border in erythroid cells...
  30. Berrozpe G, Agosti V, Tucker C, Blanpain C, Manova K, Besmer P. A distant upstream locus control region is critical for expression of the Kit receptor gene in mast cells. Mol Cell Biol. 2006;26:5850-60 pubmed
    ..Therefore, the 5' upstream hypersensitivity sites appear to be critical components of locus control region-mediated Kit gene activation in mast cells.
  31. Fang X, Xiang P, Yin W, Stamatoyannopoulos G, Li Q. Cooperativeness of the higher chromatin structure of the beta-globin locus revealed by the deletion mutations of DNase I hypersensitive site 3 of the LCR. J Mol Biol. 2007;365:31-7 pubmed
    High-level transcription of the globin genes requires the enhancement by a distant element, the locus control region (LCR)...
  32. Levings P, Zhou Z, Vieira K, Crusselle Davis V, BUNGERT J. Recruitment of transcription complexes to the beta-globin locus control region and transcription of hypersensitive site 3 prior to erythroid differentiation of murine embryonic stem cells. FEBS J. 2006;273:746-55 pubmed
    ..High-level expression of these genes is mediated by a locus control region (LCR), a powerful DNA regulatory element composed of several DNase I hypersensitive (HS) sites and located ..
  33. Wang H, Shayakhmetov D, Leege T, Harkey M, Li Q, Papayannopoulou T, et al. A capsid-modified helper-dependent adenovirus vector containing the beta-globin locus control region displays a nonrandom integration pattern and allows stable, erythroid-specific gene expression. J Virol. 2005;79:10999-1013 pubmed
    ..Toward this goal, we constructed a helper-dependent adenovirus vector carrying the beta-globin locus control region (LCR) to drive green fluorescent protein (GFP) expression, whereby the LCR-GFP cassette is flanked by adeno-..
  34. Fragkos M, Anagnou N, Tubb J, Emery D. Use of the hereditary persistence of fetal hemoglobin 2 enhancer to increase the expression of oncoretrovirus vectors for human gamma-globin. Gene Ther. 2005;12:1591-600 pubmed
    ..erythroleukemia) cells demonstrated the HPFH2 element could function synergistically with the beta-globin locus control region to enhance the expression of an Agamma-globin gene with a truncated -382 bp promoter...
  35. Feng Y, Warin R, Li T, Olivier E, Besse A, Lobell A, et al. The human beta-globin locus control region can silence as well as activate gene expression. Mol Cell Biol. 2005;25:3864-74 pubmed
    ..of integration, we demonstrate a novel chromatin context-dependent silencer activity of the beta-globin locus control region (LCR). This silencer activity requires DNase I hypersensitive sites HS2 and HS3 but not HS4...
  36. Sawado T, Halow J, Bender M, Groudine M. The beta -globin locus control region (LCR) functions primarily by enhancing the transition from transcription initiation to elongation. Genes Dev. 2003;17:1009-18 pubmed
    ..we analyzed factor recruitment and histone modification at the adult beta-globin gene in wild-type (WT)/locus control region knockout (DeltaLCR) heterozygous mice and in murine erythroleukemia (MEL) cells...
  37. Patrinos G, de Krom M, de Boer E, Langeveld A, Imam A, Strouboulis J, et al. Multiple interactions between regulatory regions are required to stabilize an active chromatin hub. Genes Dev. 2004;18:1495-509 pubmed
    The human beta-globin locus control region (LCR) is required for the maintenance of an open chromatin configuration of the locus...
  38. Wai A, Gillemans N, Raguz Bolognesi S, Pruzina S, Zafarana G, Meijer D, et al. HS5 of the human beta-globin locus control region: a developmental stage-specific border in erythroid cells. EMBO J. 2003;22:4489-500 pubmed
    ..Here, we have characterized HS5 of the human beta-globin locus control region. We have examined its tissue-specificity and assessed its insulating properties in transgenic mice using a ..
  39. Chambeyron S, Bickmore W. Does looping and clustering in the nucleus regulate gene expression?. Curr Opin Cell Biol. 2004;16:256-62 pubmed
    ..Nuclear compartments may also be involved in the post-translational modification of proteins by sumoylation and ubiquitylation. ..
  40. Ragoczy T, Telling A, Sawado T, Groudine M, Kosak S. A genetic analysis of chromosome territory looping: diverse roles for distal regulatory elements. Chromosome Res. 2003;11:513-25 pubmed
    ..Conversely, a mutant allele lacking the locus control region (LCR), which is required for high-level globin expression, was mostly coincident with the CT...
  41. Giraldo P, Martinez A, Regales L, Lavado A, García Díaz A, Alonso A, et al. Functional dissection of the mouse tyrosinase locus control region identifies a new putative boundary activity. Nucleic Acids Res. 2003;31:6290-305 pubmed
  42. Shewchuk B, Liebhaber S, Cooke N. Specification of unique Pit-1 activity in the hGH locus control region. Proc Natl Acad Sci U S A. 2002;99:11784-9 pubmed
    The human GH (hGH) gene cluster is regulated by a remote 5' locus control region (LCR). HSI, an LCR component located 14...
  43. Montiel Equihua C, Zhang L, Knight S, Saadeh H, Scholz S, Carmo M, et al. The β-globin locus control region in combination with the EF1α short promoter allows enhanced lentiviral vector-mediated erythroid gene expression with conserved multilineage activity. Mol Ther. 2012;20:1400-9 pubmed publisher
    ..of constitutively acting elongation factor 1α promoter (EFS) combined with essential elements of the locus control region of the β-globin gene (β-LCR)...
  44. Hunsaker T, Jefferson H, Morrison J, Franklin A, Shewchuk B. POU1F1-mediated activation of hGH-N by deoxyribonuclease I hypersensitive site II of the human growth hormone locus control region. J Mol Biol. 2012;415:29-45 pubmed publisher
    The human growth hormone gene (hGH-N) is regulated by a distal locus control region (LCR) composed of five deoxyribonuclease I hypersensitive sites (HSs)...
  45. Onishi Y, Kiyama R. Interaction of NF-E2 in the human beta-globin locus control region before chromatin remodeling. J Biol Chem. 2003;278:8163-71 pubmed
    ..protein NF-E2 interacts with the cognate motif at DNase I-hypersensitive site 2 of the human beta-globin locus control region in a repressive state...
  46. Irwin J, Saunier J, Niederstätter H, Strouss K, Sturk K, Diegoli T, et al. Investigation of heteroplasmy in the human mitochondrial DNA control region: a synthesis of observations from more than 5000 global population samples. J Mol Evol. 2009;68:516-27 pubmed publisher
  47. Ho Y, Tadevosyan A, Liebhaber S, Cooke N. The juxtaposition of a promoter with a locus control region transcriptional domain activates gene expression. EMBO Rep. 2008;9:891-8 pubmed publisher
    ..A 5'-remote locus control region (LCR) regulates the human growth hormone (hGH-N) gene...
  48. Ronai D, Berru M, Shulman M. The epigenetic stability of the locus control region-deficient IgH locus in mouse hybridoma cells is a clonally varying, heritable feature. Genetics. 2004;167:411-21 pubmed
    ..Our results thus show that a single-copy gene in the same chromosomal location and in the presence of the same transcription factors can exist in many different states of expression. ..
  49. Fields P, Lee G, Kim S, Bartsevich V, Flavell R. Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity. 2004;21:865-76 pubmed
    ..of the rad50 gene possessing strong enhancer activity as well as activity consistent with function as a locus control region (LCR) for the flanking Th2 cytokine genes...
  50. Bottardi S, Bourgoin V, Pierre Charles N, Milot E. Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells. Hum Mol Genet. 2005;14:493-502 pubmed
    ..Deletion of hypersensitive site 2 (HS2) at the human beta-globin locus control region can lead to abnormal epigenetic regulation of globin genes in transgenic mice...
  51. Baxter E, Cummings W, Fournier R. Formation of a large, complex domain of histone hyperacetylation at human 14q32.1 requires the serpin locus control region. Nucleic Acids Res. 2005;33:3313-22 pubmed
    ..For example, deletion of a previously identified serpin locus control region (LCR) upstream of the proximal subcluster reduces both gene expression and histone acetylation throughout ..
  52. Feng D, Kan Y. The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes. Proc Natl Acad Sci U S A. 2005;102:9896-900 pubmed
    ..that after differentiation, the p300/CREB-binding protein-associated factor is recruited by FKLF2 to the locus control region to acetylate histones 3 and 4 at the human beta-globin gene locus...
  53. Ragoczy T, Bender M, Telling A, Byron R, Groudine M. The locus control region is required for association of the murine beta-globin locus with engaged transcription factories during erythroid maturation. Genes Dev. 2006;20:1447-57 pubmed
    ..from the periphery and its association with hyperphosphorylated Pol II transcription factories require the locus control region (LCR)...