Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression.
Hop is an unusual homeodomain protein that was first identified in the developing heart where it functions downstream of Nkx2.5 to modulate cardiac gene expression. Hop functions through interactions with histone deacetylase (HDAC) 2 to mediate repression of cardiac-specific genes, and recent studies show that HDAC activity and HDAC2 expression are decreased in people with chronic obstructive pulmonary disease. Here, we show that Hop is expressed in airway epithelium coincident with HDAC2, and expression is induced by the combination of dexamethasone and cAMP in parallel with induction of surfactant protein gene expression. Hop functions in the developing pulmonary airway, acting downstream of Nkx2.1 and GATA6, to negatively regulate surfactant protein expression. Loss of Hop expression in vivo results in defective type 2 pneumocyte development with increased surfactant production and disrupted alveolar formation. Thus Hop represents a novel regulator of pulmonary maturation that is induced by glucocorticoids to mediate functionally important HDAC-dependent negative feedback regulation.
Yin
Zhan
Z
Department of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
Gonzales
Linda
L
Kolla
Venkatadri
V
Rath
Nibedita
N
Zhang
Yuzhen
Y
Lu
Min Min
MM
Kimura
Shioko
S
Ballard
Philip L
PL
Beers
Michael F
MF
Epstein
Jonathan A
JA
Morrisey
Edward E
EE
D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000502:physiology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D018398:Homeodomain Proteins; C466740:Hop protein, mouse; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases