Sonic hedgehog signals hinder the transcriptional network necessary for pancreatic endoderm formation from human embryonic stem cells
Autor: | Prasad Pethe, Aparna Khanna, Niloufer P. Dumasia |
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Rok vydání: | 2021 |
Předmět: |
animal structures
Transcription Genetic Cellular differentiation Human Embryonic Stem Cells Polycomb-Group Proteins Biology Models Biological 03 medical and health sciences Endoderm formation Genetics medicine Humans Gene Regulatory Networks Hedgehog Proteins Sonic hedgehog Pancreas Hedgehog Body Patterning 030304 developmental biology 0303 health sciences Endoderm Gene Expression Regulation Developmental Cell Differentiation Cell Biology Hedgehog signaling pathway Cell biology medicine.anatomical_structure BMI1 embryonic structures biology.protein PDX1 Bile Ducts Signal Transduction |
Zdroj: | Genes to Cells. 26:282-297 |
ISSN: | 1365-2443 1356-9597 |
DOI: | 10.1111/gtc.12839 |
Popis: | Hedgehog morphogens govern multiple aspects of pancreas organogenesis and functioning with diverse outcomes across species. Although most current differentiation protocols repress Sonic hedgehog (SHH) signals during in vitro endocrine specification, the role and mechanisms through which the SHH pathway antagonizes pancreas development during in vitro human embryonic stem (hES) cell differentiation remain unclear. We modulated SHH signaling at transitory stages of hES cell-derived pancreatic progenitors and analyzed the effect on cellular fate decisions. We identify the Hedgehog pathway as a negative regulator of pancreatic endoderm formation through up-regulation of a set of pancreatobiliary markers required for ductal specification, including SOX17, FOXA2, HNF1β, HNF6, PDX1, and SOX9. Surprisingly, active Hedgehog signals impeded a group of pancreatic epithelium markers, including HNF4α, HHEX, PAX6, and PTF1α. To understand how SHH signals repress the transcription of these specific markers, we analyzed Polycomb group proteins. We found differential expression of Polycomb Repressive Complex 1 subunit, BMI1 upon Shh pathway modulation in the pancreatic progenitors. Ectopic activation of Sonic hedgehog results in over-expression of BMI1 and its associated repressive histone mark, H2AK119Ub1, in the multipotent progenitors. Our data suggest that Sonic hedgehog restricts the pancreatic differentiation program by limiting progenitor cells acquiring pancreatic epithelial fates and instead promotes pancreatobiliary differentiation. We further provide mechanistic cues of an association between Hedgehog signaling and epigenetic silencers during pancreatic lineage decisions. |
Databáze: | OpenAIRE |
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