Slow, stochastic transgene repression with properties of a timer.
BACKGROUND
When gene expression varies unpredictably between genetically identical organisms, this is sometimes ascribed as stochastic. With the prevalence of retroviral vectors, stochastic repression is often observed and can complicate the interpretation of outcomes. But it may also faithfully reflect characteristics of sites in the genome.


RESULTS
We created and identified several cell clones in which, within a given cell, retroviral transcription of a transgene was repressed heritably and essentially irreversibly. This repression was relatively slow; total repression in all cells took months. We observed the dynamics of repression and found that they were ergodic, that is, tending with a probability to a final state independent of previous conditions. Different positions of the transgene in the genome demonstrated different dynamics. At a position on mouse chromosome 9, repression abided by near perfect first-order kinetics and was highly reproducible, even under conditions where the number of cell generations per day varied.


CONCLUSIONS
We propose that such a cell division independent 'off' mechanism could play a role in endogenous gene expression, potentially providing an epigenetically based timer for extended periods.
Wang
Clifford L
CL
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA. cliff.wang@ucsf.edu
Yang
Desirée C
DC
Wabl
Matthias
M
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D051379:Mice; D013269:Stochastic Processes; D019076:Transgenes
D006657:Histones; D049452:Green Fluorescent Proteins