Positive and negative transcriptional states of a variegating immunoglobulin heavy chain (IgH) locus are maintained by a cis-acting epigenetic mechanism.
J Immunol
; 169(12): 6919-27, 2002 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-12471125
ABSTRACT
Analyses of transgene expression have defined essential components of a locus control region (LCR) in the J(H)-C(mu) intron of the IgH locus. Targeted deletion of this LCR from the endogenous IgH locus of hybridoma cells results in variegated expression, i.e., cells can exist in two epigenetically inherited states in which the Ig(mu) H chain gene is either active or silent; the active or silent state is typically transmitted to progeny cells through many cell divisions. In principle, cells in the two states might differ either in their content of specific transcription factors or in a cis-acting feature of the IgH locus. To distinguish between these mechanisms, we generated LCR-deficient, recombinant cell lines in which the Ig(mu) H chain genes were distinguished by a silent mutation and fused cells in which the mu gene was active with cells in which mu was silent. Our analysis showed that both parental active and silent transcriptional states were preserved in the hybrid cell, i.e., that two alleles of the same gene in the same nucleus can exist in two different states of expression through many cell divisions. These results indicate that the expression of the LCR-deficient IgH locus is not fully determined by the cellular complement of transcription factors, but is also subject to a cis-acting, self-propagating, epigenetic mark. The methylation inhibitor, 5-azacytidine, reactivated IgH in cells in which this gene was silent, suggesting that methylation is part of the epigenetic mark that distinguishes silent from active transcriptional states.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transcripción Genética
/
Intrones
/
Cadenas Pesadas de Inmunoglobulina
/
Cadenas mu de Inmunoglobulina
/
Región de Control de Posición
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2002
Tipo del documento:
Article
País de afiliación:
Canadá