In order to specify the correct lineage at the correct time, the developing embryo must maintain tight control over the gene regulatory networks that enact these changes. Sall4 has long been associated with the regulation of embryonic stem cell (ESC) self-renewal and differentiation; however, teasing out its precise role has been difficult. Now, on p. 3074, Brian Hendrich and colleagues present a comprehensive analysis of the role of Sall4 in self-renewal and differentiation, and shed light on the nature of its interaction with the NuRD complex during these events. Using a series of phenotypical and transcriptional analyses of double Sall4/1 knockout mouse ESCs (mESCs), the authors show that Sall1 and Sall4 are dispensable for ESC pluripotency but are required to repress neuronal differentiation. Remarkably, the authors observed the spontaneous production of neurons alongside self-renewing mESCs in the double knockout mESCs. Genome-wide analyses demonstrate that, although a small proportion of Sall4 does indeed interact with NuRD, Sall4 neither recruits nor functions through the NuRD complex. Rather, Sall4 is seen to bind to enhancer sequences along with the pluripotency-associated transcription factors Pou5f1, Nanog, Klf4 and Esrrb, which can result in either gene activation or repression. Together, these data shed light on a number of previously unresolved issues with regard to the function of Sall4 in mammalian development.
- © 2016. Published by The Company of Biologists Ltd