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Kerschner JL, Paranjapye A, NandyMazumdar M, et al. OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements. Dev Dyn. 2021;250(5):684-700doi: 10.1002/dvdy.293.
Kerschner, J. L., Paranjapye, A., NandyMazumdar, M., Yin, S., Leir, S. H., & Harris, A. (2021). OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements. Developmental dynamics : an official publication of the American Association of Anatomists, 250(5), 684-700. https://doi.org/10.1002/dvdy.293
Kerschner, Jenny L, et al. "OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements." Developmental dynamics : an official publication of the American Association of Anatomists vol. 250,5 (2021): 684-700. doi: https://doi.org/10.1002/dvdy.293
Kerschner JL, Paranjapye A, NandyMazumdar M, Yin S, Leir SH, Harris A. OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements. Dev Dyn. 2021 May;250(5):684-700. doi: 10.1002/dvdy.293. Epub 2021 Jan 26. PMID: 33386644.
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Dev Dyn. 2021 May;250(5):684-700. doi: 10.1002/dvdy.293. Epub 2021 Jan 26.

OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements.

Developmental dynamics : an official publication of the American Association of Anatomists

Jenny L Kerschner, Alekh Paranjapye, Monali NandyMazumdar, Shiyi Yin, Shih-Hsing Leir, Ann Harris

Affiliations

  1. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

PMID: 33386644 DOI: 10.1002/dvdy.293

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.

© 2021 American Association of Anatomists.

Keywords: airway epithelial development; cis-regulatory elements; cystic fibrosis; gene regulation; iPSC differentiation

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