The epigenetic stability of the locus control region-deficient IgH locus in mouse hybridoma cells is a clonally varying, heritable feature.
Cis-acting elements such as enhancers and locus control regions (LCRs) prevent silencing of gene expression. We have shown previously that targeted deletion of an LCR in the immunoglobulin heavy-chain (IgH) locus creates conditions in which the immunoglobulin micro heavy chain gene can exist in either of two epigenetically inherited states, one in which micro expression is positive and one in which micro expression is negative, and that the positive and negative states are maintained by a cis-acting mechanism. As described here, the stability of these states, i.e., the propensity of a cell to switch from one state to the other, varied among subclones and was an inherited, clonal feature. A similar variation in stability was seen for IgH loci that both lacked and retained the matrix attachment regions associated with the LCR. Our analysis of cell hybrids formed by fusing cells in which the micro expression had different stabilities indicated that stability was also determined by a cis-acting feature of the IgH locus. 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.
Ronai
Diana
D
Immunology Department, University of Toronto, Toronto, Ontario M5S 1A8, Canada. dronai@aecom.yu.edu
Berru
Maribel
M
Shulman
Marc J
MJ
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D018899:CpG Islands; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005803:Genes, Immunoglobulin / Q000235:genetics*; D014644:Genetic Variation; D006825:Hybridomas / Q000276:immunology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007438:Introns; D019901:Locus Control Region / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007143:Immunoglobulin Heavy Chains; D011994:Recombinant Proteins; C012589:trichostatin A; D012313:RNA; D001374:Azacitidine