OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements.
Dev Dyn
; 250(5): 684-700, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33386644
ABSTRACT
BACKGROUND:
Cell-specific and developmental mechanisms contribute to expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene; however, its developmental regulation is poorly understood. Here we use human induced pluripotent stem cells differentiated into pseudostratified airway epithelial cells to study these mechanisms.RESULTS:
Changes in gene expression and open chromatin profiles were investigated by RNA-seq and ATAC-seq, and revealed that alterations in CFTR expression are associated with differences in stage-specific open chromatin. Additionally, two novel open chromatin regions, at +19.6 kb and +22.6 kb 3' to the CFTR translational stop signal, were observed in definitive endoderm (DE) cells, prior to an increase in CFTR expression in anterior foregut endoderm (AFE) cells. Chromatin studies in DE and AFE cells revealed enrichment of active enhancer marks and occupancy of OTX2 at these sites in DE cells. Loss of OTX2 in DE cells alters histone modifications across the CFTR locus and results in a 2.5-fold to 5-fold increase in CFTR expression. However, deletion of the +22.6 kb site alone does not affect CFTR expression in DE or AFE cells.CONCLUSIONS:
These results suggest that a network of interacting cis-regulatory elements recruit OTX2 to the locus to impact CFTR expression during early endoderm differentiation.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
/
Regulador de Condutância Transmembrana em Fibrose Cística
/
Mucosa Respiratória
/
Fatores de Transcrição Otx
/
Elementos Reguladores de Transcrição
Limite:
Humans
Idioma:
En
Revista:
Dev Dyn
Assunto da revista:
ANATOMIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos