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In development, lineage-restricted transcription factors simultaneously promote differentiation while repressing alternative fates. Molecular dissection of this process has been challenging as transcription factor loci are regulated by many  trans -acting factors functioning through dispersed  cis  elements. It is not understood whether these elements function collectively to confer transcriptional regulation, or individually to control specific aspects of activation or repression, such as initiation versus maintenance. Here, we have analyzed  cis  element regulation of the critical hematopoietic factor  Gata2 , which is expressed in early precursors and repressed as GATA-1 levels rise during terminal differentiation. We engineered mice lacking a single  cis  element −1.8 kb upstream of the  Gata2  transcriptional start site. Although  Gata2  is normally repressed in late-stage erythroblasts, the −1.8 kb mutation unexpectedly resulted in reactivated  Gata2  transcription, blocked differentiation, and an aberrant lineage-specific gene expression pattern. Our findings demonstrate that the −1.8 kb site selectively maintains repression, confers a specific histone modification pattern and expels RNA Polymerase II from the locus. These studies reveal how an individual  cis  element establishes a normal developmental program via regulating specific steps in the mechanism by which a critical transcription factor is repressed.

A Single cis Element Maintains Repression of the Key Developmental Regulator Gata2