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A small-molecule screen reveals that HSP90β promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover.
- Source :
-
Development (Cambridge, England) [Development] 2017 May 15; Vol. 144 (10), pp. 1764-1774. Date of Electronic Publication: 2017 Mar 30. - Publication Year :
- 2017
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Abstract
- We have previously shown that the transcription factor HNF4A is required for the formation of hepatic progenitor cells from endoderm that has been derived from human induced pluripotent stem cells (iPSCs). We reasoned that we could uncover regulatory pathways with new roles in hepatocyte differentiation by identifying cellular processes that regulate HNF4A. We therefore performed a screen of 1120 small molecules with well-characterized mechanisms of action to detect those that affect the abundance of HNF4A in iPSC-derived hepatic progenitor cells. This approach uncovered several small molecules that depleted HNF4A. Of those, we chose to focus on an inhibitor of heat shock protein 90 beta (HSP90β). We show that mutation of the gene encoding HSP90β represses hepatocyte differentiation during the formation of hepatocytes from iPSCs. We reveal that HSP90β, although dispensable for expression of HNF4A mRNA, directly interacts with HNF4A protein to regulate its half-life. Our results demonstrate that HSP90β has an unappreciated role in controlling hepatic progenitor cell formation and highlight the efficiency of using small-molecule screens during the differentiation of iPSCs to reveal new molecular mechanisms that control hepatocyte formation.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2017. Published by The Company of Biologists Ltd.)
- Subjects :
- Cells, Cultured
HSP90 Heat-Shock Proteins metabolism
Half-Life
Humans
Liver cytology
Protein Denaturation
Cell Differentiation genetics
Endoderm cytology
HSP90 Heat-Shock Proteins physiology
Hepatocyte Nuclear Factor 4 metabolism
Hepatocytes physiology
High-Throughput Screening Assays methods
Induced Pluripotent Stem Cells physiology
Small Molecule Libraries analysis
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 144
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 28360131
- Full Text :
- https://doi.org/10.1242/dev.146845