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First published online 29 June 2005
doi: 10.1242/dev.01923
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1 Department of Pediatrics and Molecular Medicine Program, University of
California, Parnassus Avenue, San Francisco, CA 94143, USA
2 Department of Cell and Tissue Biology, University of California, Parnassus
Avenue, San Francisco, CA 94143, USA
3 Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8700 Beverly
Boulevard, West Hollywood, CA 90048, USA
4 Howard Hughes Medical Institute, Abramson Family Cancer Research Institute,
University of Pennsylvania, Philadelphia, PA 19104, USA
5 Department of Cell and Developmental Biology, University of Pennsylvania,
Philadelphia, PA 19104, USA
6 Abramson Cancer Research Institute, University of Pennsylvania, Philadelphia,
PA 19104, USA
7 Obstetrics, Gynecology and Reproductive Sciences, University of California,
Parnassus Avenue. San Francisco, CA 94143, USA
8 Department of Pharmaceutical Chemistry, University of California, Parnassus
Avenue, San Francisco, CA 94143, USA
9 Department of Anatomy, University of California, Parnassus Avenue, San
Francisco, CA 94143, USA
* Author for correspondence (e-mail: sfisher{at}cgl.ucsf.edu)
Accepted 31 May 2005
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor
composed of HIF
and the arylhydrocarbon receptor nuclear translocator
(ARNT/HIF1ß). Previously, we have reported that ARNT function is required
for murine placental development. Here, we used cultured trophoblast stem (TS)
cells to investigate the molecular basis of this requirement. In
vitro, wild-type TS cell differentiation is largely restricted to
spongiotrophoblasts and giant cells. Interestingly, Arnt-null TS
cells differentiated into chorionic trophoblasts and syncytiotrophoblasts, as
demonstrated by their expression of Tfeb, glial cells missing 1 (Gcm1) and the
HIV receptor CXCR4. During this process, a region of the differentiating
Arnt-null TS cells underwent granzyme B-mediated apoptosis,
suggesting a role for this pathway in murine syncytiotrophoblast turnover.
Surprisingly, HIF1 and HIF2 were induced during TS cell
differentiation in 20% O2; additionally, pVHL levels were modulated
during the same time period. These results suggest that oxygen-independent HIF
functions are crucial to this differentiation process. As histone deacetylase
(HDAC) activity has been linked to HIF-dependent gene expression, we
investigated whether ARNT deficiency affects this epigenetic regulator.
Interestingly, Arnt-null TS cells had reduced HDAC activity,
increased global histone acetylation, and altered class II HDAC subcellular
localization. In wild-type TS cells, inhibition of HDAC activity recapitulated
the Arnt-null phenotype, suggesting that crosstalk between the HIFs
and the HDACs is required for normal trophoblast differentiation. Thus, the
HIFs play important roles in modulating the developmental plasticity of stem
cells by integrating physiological, transcriptional and epigenetic inputs.
Key words: HIF, ARNT, HDAC, Stem cell, Syncytiotrophoblast, Placenta, Mouse
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