β-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice

Raouf Alami, John M. Greally, Keiji Tanimoto, Steven Hwang, Yong Qing Feng, James D. Engel, Steven Fiering, Eric E. Bouhassira

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Expression of a construct integrated at different genomic locations often varies because of position effects that have been subcategorized as stable (decreased level of expression) and variegating (decreased proportion of expressing cells). It is well established that locus control regions (LCRs) generally overcome position effects in transgenes. However, whether stable and variegated position effects are equally overcome by an intact LCR has not been determined. We report that single-copy yeast artificial chromosome transgenes containing an unmodified human β-globin locus were not subject to detectable stable position effects but did undergo mild to severe variegating position effects at three of the four non-centromeric integration sites tested. We also find that, at a given integration site, the distance and the orientation of the LCR relative to the regulated gene contributes to the likelihood of variegating position effects, and can affect the magnitude of its transcriptional enhancement. DNase I hypersensitive site (HSS) formation varies with the proportion of expressing cells, not the level of gene expression, suggesting that silencing of the transgene is associated with a lack of HSS formation in the LCR region. We conclude that transcriptional enhancement and variegating position effects are caused by fundamentally different but interdependent mechanisms.

Original languageEnglish (US)
Pages (from-to)631-636
Number of pages6
JournalHuman molecular genetics
Volume9
Issue number4
StatePublished - Mar 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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