Dissecting the transcriptional regulatory network for early T-cell commitment

Abstract

Multipotent precursors proliferating in the thymus become committed to a T-cell fate when their access to alternative cell fates is intrinsically and unconditionally closed. This process involves very dynamic changes in transcription factor expression and activity: PU.1 and other factors expressed in multipotent progenitors are downregulated and are usually permanently silenced, while T-cell transcription factors, especially Bcl11b, are sharply activated. The abrupt activation of Bcl11b from a silent state is not only a landmark in T-cell differentiation, marking commitment, but also a functional contributor to commitment. Key target genes affected by Bcl11b function at this particular stage will be described: many of them appear to be under the control of Bcl11b as a repressor. Recent proteomic characterization of Bcl11b-containing protein complexes indicates the corepressor and coactivator partners that it uses to mediate different types of regulatory activity at different genomic sites. Since Bcl11b is such a powerful factor, a central question is how the onset of expression of Bcl11b itself is controlled. The talk will describe the combination of trans-acting factors that are needed to open the Bcl11b locus and activate it, and show that these factors each play slightly different temporal and functional roles in the activation process. Interestingly, evidence will also be shown for an epigenetic component of Bcl11b regulation that further slows its activation but helps to make it irreversible.

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