Synthetic Transcription Factors Switch from Local to Long-Range Control during Cell Differentiation

Genes, including
promoters and enhancers, are regulated by short-
and long-range interactions in higher eukaryotes. It is unclear how
mammalian gene expression subject to such a combinatorial regulation
can be controlled by synthetic transcription factors (TF). Here, we
studied how synthetic TALE transcriptional activators and repressors
affect the expression of genes in a gene array during cellular differentiation.
The protocadherin gene array is silent in mouse embryonic stem (ES)
and neuronal progenitor cells. The TALE transcriptional activator
recruited to a promoter activates specifically the target gene in
ES cells. Upon differentiation into neuronal progenitors, the transcriptional
regulatory logic changes: the same activator behaves like an enhancer,
activating distant genes in a correlated, stochastic fashion. The
long-range effect is reflected by the alterations in CpG methylation.
Our findings reveal the limits of precision and the opportunities
in the control of gene expression for TF-based therapies in cells
of various differentiation stages.