Activation of the beta globin locus by transcription factors and chromatin modifiers.
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.
McMorrow
T
T
Department of Cell Biology and Genetics, Medical Genetics Centre, Faculty of Medicine, Erasmus University Rotterdam.
van den Wijngaard
A
A
Wollenschlaeger
A
A
van de Corput
M
M
Monkhorst
K
K
Trimborn
T
T
Fraser
P
P
van Lohuizen
M
M
Jenuwein
T
T
Djabali
M
M
Philipsen
S
S
Grosveld
F
F
Milot
E
E
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D020868:Gene Silencing; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051741:Kruppel-Like Transcription Factors; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; C570426:Cbx2 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D012313:RNA; D005914:Globins; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D063150:Polycomb Repressive Complex 1; D003850:Deoxyribonuclease I; D015719:Single-Strand Specific DNA and RNA Endonucleases