Abstract

Sets of conserved transcription factors are responsible for conserved tissue-specific transcription, yet transcription factor binding events diverge rapidly between closely related species (1,2). To decouple the distinct molecular mechanisms that direct transcription factor binding and gene expression we investigated tissue-specific transcriptional regulation in a mouse containing human chromosome 21 (the Tc1 mouse) (3). Gene expression and transcription intiation occurred at similar syntenic genes in hepatocytes from humans, wild-type mice, and Tc1 mice; however, the transcription initiation occurring in other genomic regions was specified by species-specific genetic sequences. Characterization of transcription factor binding in the Tc1 mice revealed that tissue-specific transcriptional regulation is directed almost exclusively by species-specific genetic sequences. High-resolution interrogation of transcription factor binding in Tc1 mice using deep sequencing established the genetic sequences that re-direct tissue-specific transcription factor binding in an entirely uniform nuclear environment. Divergent patterns of transcriptional regulation coded in genetic sequence can thus be transplanted between species to recapitulate conserved transcription in homologous tissues.