Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia
Carolina Pinzon-Guzman, Sreedhara Sangadala, Katherine M. Riera, Evgenya Y. Popova, Elizabeth Manning, Won Jae Huh, Matthew S. Alexander, Julia S. Shelton, Scott D. Boden, James R. Goldenring
Carolina Pinzon-Guzman, Sreedhara Sangadala, Katherine M. Riera, Evgenya Y. Popova, Elizabeth Manning, Won Jae Huh, Matthew S. Alexander, Julia S. Shelton, Scott D. Boden, James R. Goldenring
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Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia

Abstract

Esophageal atresia (EA/TEF) is a common congenital abnormality present in 1 of 4000 births. Here we show that atretic esophagi lack Noggin (NOG) expression, resulting in immature esophagus that contains respiratory glands. Moreover, when using mouse esophageal organoid units (EOUs) or tracheal organoid units (TOUs) as a model of foregut development and differentiation in vitro, NOG determines whether foregut progenitors differentiate toward esophageal or tracheal epithelium. These results indicate that NOG is a critical regulator of cell fate decisions between esophageal and pulmonary morphogenesis, and its lack of expression results in EA/TEF.

Authors

Carolina Pinzon-Guzman, Sreedhara Sangadala, Katherine M. Riera, Evgenya Y. Popova, Elizabeth Manning, Won Jae Huh, Matthew S. Alexander, Julia S. Shelton, Scott D. Boden, James R. Goldenring

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Figure 7

DNA methylation of NOG locus is increased in patients with EA/TEF.

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DNA methylation of NOG locus is increased in patients with EA/TEF. (A) C...
(A) Combined genome-wide tracks for NOG gene locus from UCSC human genome browser hg18. From top to bottom: CpG islands are in dark green; NOG transcript is in black; DNA conserved in mammals is dark blue; invertebrates is in black. ENCODE BROAD chromatin segmentation by HMM in H1-hESC: weak transcription is in light green, weak/poised enhancer is in yellow, repressed chromatin is in gray, and poised promoter is in purple. Regulatory potential of DNA is light blue. The 3 DNA areas of NOG locus that were assessed for DNA methylation are marked as numbered small boxes at the bottom of the panel. 1, exon of NOG gene; 2, promoter of NOG; 3, upstream regulatory region. (B) Lollipop plots of DNA methylation of NOG locus CpG islands from 16 EA/TEF patients and 3 controls. Promoter, exon, and the region 10 kb upstream of promoter were analyzed. (C) Quantification of percentage of CpG islands methylated (n = 6–12), **P < 0.005.