Abstract
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.
Highlights
Metazoan development is characterized by complex transcriptional programs specified by gene regulatory networks [1,2]
Different cell types are formed and maintained by proteins called transcription factors that directly bind to specific DNA sequences to activate or repress gene expression
While numerous DNA sequences bound by transcription factors are established, many questions remain unanswered regarding how they function at specific sites located at distinct chromosomal regions
Summary
Metazoan development is characterized by complex transcriptional programs specified by gene regulatory networks [1,2]. Transcription factors in these networks occupy specific cis elements at target gene loci where they modulate chromatin remodeling and modification, and thereby transcription. Models of gene regulation have led to an attractive paradigm in which repression occurs in sequential stages of increasing stability [4]. While transcription factors bind and recruit chromatin-modifying and remodeling proteins, the relative contribution of individual cis elements residing within clusters of cis elements to the transcriptional control of endogenous loci is incompletely understood. GATA factor cross-regulation represents an instructive model system for investigating the contribution of individual cis elements to the initiation and maintenance of transcriptional repression. GATA-1 directly represses Gata transcription via displacing GATA-2 from chromatin sites at its own locus, a process termed a ‘‘GATA Switch’’ [6,7]
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