Editors' ChoiceDevelopment

Prepatterned Progenitors

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Science Signaling  24 May 2011:
Vol. 4, Issue 174, pp. ec150
DOI: 10.1126/scisignal.4174ec150

Epigenetic regulation of gene expression, including histone modification, plays an important role in cell type specification. In the early mouse embryo, endodermal cells of the ventral foregut give rise to both liver and pancreas progenitors. Xu et al. identified distinct histone modification patterns associated with liver- and pancreas-specific genes in undifferentiated, multipotent ventral foregut endodermal cells, implying that these cells are characterized by lineage-specific chromatin structures before differentiation. The histone acetyltransferase P300 was required for acetylation of liver-specific gene regulatory elements and for optimal specification of hepatoblasts. Hepatoblast formation was greatly reduced in mice heterozygous for P300 deficiency (P300+/–) and in mice in which P300 was targeted by RNA interference, but endodermal specification in these animals was not affected. The methyltransferase EZH2 was also required for liver specification, because conditional knockout of Ezh2 resulted in the increased production of pancreatic cells at the expense of hepatocyte production. Bone morphogenetic protein (BMP) signaling promotes the liver fate in early ventral endoderm, and treating cultured embryos with BMP4 increased histone acetylation at liver regulatory elements. The BMP signaling effector Smad4, a transcription factor that interacts with P300 and is present at liver regulatory elements, was required for acetylation of histone H3 in cells expressing a liver-specific marker. Hepatocyte formation was not completely eliminated in Ezh2, Smad4, or P300+/– mutants, indicating that chromatin modifications were not absolute regulators of the choice between liver and pancreas fates but rather modulated the balance between the specification of the two progenitor populations. The authors thus propose that distinct chromatin prepatterns influence cell fate decisions and so may be important in other contexts by influencing the developmental potential of multipotent cells.

C.-R. Xu, P. A. Cole, D. J. Meyers, J. Kormish, S. Dent, K. S. Zaret, Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science 332, 963–966 (2011). [Abstract] [Full Text]

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