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OTX2 regulates CFTR expression during endoderm differentiation and occupies 3′ cis‐ regulatory elements
Author(s) -
Kerschner Jenny L.,
Paranjapye Alekh,
NandyMazumdar Monali,
Yin Shiyi,
Leir ShihHsing,
Harris Ann
Publication year - 2021
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.293
Subject(s) - endoderm , biology , chromatin , cystic fibrosis transmembrane conductance regulator , microbiology and biotechnology , cellular differentiation , regulation of gene expression , histone , cystic fibrosis , genetics , gene
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.