title: Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.
abstract: The mechanisms that govern the maintenance and differentiation of tissue-specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by derepression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell-cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell-cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue-specific progenitor activity during development and regeneration.
authors: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Yi
authors: Y
authors: Wang
authors: Ying
authors: Y
authors: Tian
authors: Michael P
authors: MP
authors: Morley
authors: Min M
authors: MM
authors: Lu
authors: Francesco J
authors: FJ
authors: Demayo
authors: Eric N
authors: EN
authors: Olson
authors: Edward E
authors: EE
authors: Morrisey
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000502:physiology; D056284:Histone Deacetylase 1 / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000502:physiology*; D008168:Lung / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; C527783:Sox2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2