Activation of the Beta Globin Locus by Transcription Factors and Chromatin Modifiers

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2000 Sep 16

PMID 10990462

Citations 13

Authors

T McMorrow

A van den Wijngaard

A Wollenschlaeger

M van de Corput

K Monkhorst

T Trimborn

P Fraser

M van Lohuizen

T Jenuwein

M Djabali

S Philipsen

F Grosveld

E Milot

Affiliations

Soon will be listed here.

Abstract

Locus control regions (LCRs) alleviate chromatin-mediated transcriptional repression. Incomplete LCRs partially lose this property when integrated in transcriptionally restrictive genomic regions such as centromeres. This frequently results in position effect variegation (PEV), i.e. the suppression of expression in a proportion of the cells. Here we show that this PEV is influenced by the heterochromatic protein SUV39H1 and by the Polycomb group proteins M33 and BMI-1. A concentration variation of these proteins modulates the proportion of cells expressing human globins in a locus-dependent manner. Similarly, the transcription factors Sp1 or erythroid Krüppel-like factor (EKLF) also influence PEV, characterized by a change in the number of expressing cells and the chromatin structure of the locus. However, in contrast to results obtained in a euchromatic locus, EKLF influences the expression of the gamma- more than the beta-globin genes, suggesting that the relief of silencing is caused by the binding of EKLF to the LCR and that genes at an LCR proximal position are more likely to be in an open chromatin state than genes at a distal position.

Citing Articles

Differential requirement of a distal regulatory region for pre-initiation complex formation at globin gene promoters.

Ross J, Bottardi S, Bourgoin V, Wollenschlaeger A, Drobetsky E, Trudel M Nucleic Acids Res. 2009; 37(16):5295-308.

PMID: 19567738 PMC: 2760785. DOI: 10.1093/nar/gkp545.

Subcellular transport of EKLF and switch-on of murine adult beta maj globin gene transcription.

Shyu Y, Lee T, Wen S, Chen H, Hsiao W, Chen X Mol Cell Biol. 2007; 27(6):2309-23.

PMID: 17242208 PMC: 1820495. DOI: 10.1128/MCB.01875-06.

Alterations in expression and chromatin configuration of the alpha hemoglobin-stabilizing protein gene in erythroid Kruppel-like factor-deficient mice.

Pilon A, Nilson D, Zhou D, Sangerman J, Townes T, Bodine D Mol Cell Biol. 2006; 26(11):4368-77.

PMID: 16705186 PMC: 1489081. DOI: 10.1128/MCB.02216-05.

The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes.

Feng D, Kan Y Proc Natl Acad Sci U S A. 2005; 102(28):9896-900.

PMID: 15998736 PMC: 1174987. DOI: 10.1073/pnas.0502041102.

The human beta-globin locus control region can silence as well as activate gene expression.

Feng Y, Warin R, Li T, Olivier E, Besse A, Lobell A Mol Cell Biol. 2005; 25(10):3864-74.

PMID: 15870261 PMC: 1087713. DOI: 10.1128/MCB.25.10.3864-3874.2005.

References

Dillon N, Trimborn T, Strouboulis J, Fraser P, Grosveld F . The effect of distance on long-range chromatin interactions. Mol Cell. 1998; 1(1):131-9. DOI: 10.1016/s1097-2765(00)80014-3. View

Grosveld F . Activation by locus control regions?. Curr Opin Genet Dev. 1999; 9(2):152-7. DOI: 10.1016/S0959-437X(99)80023-9. View

Saurin A, Shiels C, Williamson J, Satijn D, Otte A, Sheer D . The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J Cell Biol. 1998; 142(4):887-98. PMC: 2132874. DOI: 10.1083/jcb.142.4.887. View

Gillemans N, Tewari R, Lindeboom F, Rottier R, De Wit T, Wijgerde M . Altered DNA-binding specificity mutants of EKLF and Sp1 show that EKLF is an activator of the beta-globin locus control region in vivo. Genes Dev. 1998; 12(18):2863-73. PMC: 317172. DOI: 10.1101/gad.12.18.2863. View

Naar A, Beaurang P, Robinson K, Oliner J, Avizonis D, Scheek S . Chromatin, TAFs, and a novel multiprotein coactivator are required for synergistic activation by Sp1 and SREBP-1a in vitro. Genes Dev. 1998; 12(19):3020-31. PMC: 317191. DOI: 10.1101/gad.12.19.3020. View

Guy L, Kothary R, Wall L . Position effects in mice carrying a lacZ transgene in cis with the beta-globin LCR can be explained by a graded model. Nucleic Acids Res. 1997; 25(21):4400-7. PMC: 147026. DOI: 10.1093/nar/25.21.4400. View

Kioussis D, Festenstein R . Locus control regions: overcoming heterochromatin-induced gene inactivation in mammals. Curr Opin Genet Dev. 1997; 7(5):614-9. DOI: 10.1016/s0959-437x(97)80008-1. View

Brown K, Guest S, Smale S, Hahm K, MERKENSCHLAGER M, Fisher A . Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell. 1997; 91(6):845-54. DOI: 10.1016/s0092-8674(00)80472-9. View

Sinclair D, Clegg N, Antonchuk J, Milne T, Stankunas K, Ruse C . Enhancer of Polycomb is a suppressor of position-effect variegation in Drosophila melanogaster. Genetics. 1998; 148(1):211-20. PMC: 1459761. DOI: 10.1093/genetics/148.1.211. View

10.

van Lohuizen M . Functional analysis of mouse Polycomb group genes. Cell Mol Life Sci. 1998; 54(1):71-9. PMC: 11147254. DOI: 10.1007/s000180050126. View

11.

Jenuwein T, Laible G, Dorn R, Reuter G . SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell Mol Life Sci. 1998; 54(1):80-93. PMC: 11147257. DOI: 10.1007/s000180050127. View

12.

Tewari R, Gillemans N, Wijgerde M, Nuez B, von Lindern M, Grosveld F . Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region. EMBO J. 1998; 17(8):2334-41. PMC: 1170576. DOI: 10.1093/emboj/17.8.2334. View

13.

Lyko F, Paro R . Chromosomal elements conferring epigenetic inheritance. Bioessays. 1999; 21(10):824-32. DOI: 10.1002/(SICI)1521-1878(199910)21:10<824::AID-BIES4>3.0.CO;2-U. View

14.

Francastel C, Walters M, Groudine M, Martin D . A functional enhancer suppresses silencing of a transgene and prevents its localization close to centrometric heterochromatin. Cell. 1999; 99(3):259-69. DOI: 10.1016/s0092-8674(00)81657-8. View

15.

Festenstein R, Fox M, Roderick K, Tolaini M, Norton T, Saveliev A . Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context-dependent manner. Nat Genet. 1999; 23(4):457-61. DOI: 10.1038/70579. View

16.

Aagaard L, Schmid M, Warburton P, Jenuwein T . Mitotic phosphorylation of SUV39H1, a novel component of active centromeres, coincides with transient accumulation at mammalian centromeres. J Cell Sci. 2000; 113 ( Pt 5):817-29. DOI: 10.1242/jcs.113.5.817. View

17.

Alami R, Greally J, Tanimoto K, Hwang S, Feng Y, Engel J . Beta-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice. Hum Mol Genet. 2000; 9(4):631-6. DOI: 10.1093/hmg/9.4.631. View

18.

Melcher M, Schmid M, Aagaard L, Selenko P, Laible G, Jenuwein T . Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin organization, chromosome segregation, and mitotic progression. Mol Cell Biol. 2000; 20(10):3728-41. PMC: 85674. DOI: 10.1128/MCB.20.10.3728-3741.2000. View

19.

Grosveld F, Van Assendelft G, Greaves D, Kollias G . Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987; 51(6):975-85. DOI: 10.1016/0092-8674(87)90584-8. View

20.

Locke J, Kotarski M, Tartof K . Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect. Genetics. 1988; 120(1):181-98. PMC: 1203489. DOI: 10.1093/genetics/120.1.181. View