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CDX2 dose-dependently influences the gene regulatory network underlying human extraembryonic mesoderm development.
Bulger, Emily A; McDevitt, Todd C; Bruneau, Benoit G.
Affiliation
  • Bulger EA; Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • McDevitt TC; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, 94158, USA.
  • Bruneau BG; Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
Biol Open ; 13(3)2024 Mar 01.
Article in En | MEDLINE | ID: mdl-38451093
ABSTRACT
Loss of Cdx2 in vivo leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure critical for nutrient delivery and waste removal in the early embryo. Here, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development. By engineering human induced pluripotent stem cells (hiPSCs) consisting of wild-type (WT), heterozygous (CDX2-Het), and homozygous null CDX2 (CDX2-KO) genotypes, differentiating these cells in a 2D gastruloid model, and subjecting these cells to single-nucleus RNA and ATAC sequencing, we identify several pathways that are dose-dependently regulated by CDX2 including VEGF and non-canonical WNT. snATAC-seq reveals that CDX2-Het cells retain a WT-like chromatin accessibility profile, suggesting accessibility alone is not sufficient to drive this variability in gene expression. Because the loss of CDX2 or TBXT phenocopy one another in vivo, we compared differentially expressed genes in our CDX2-KO to those from TBXT-KO hiPSCs differentiated in an analogous experiment. This comparison identifies several communally misregulated genes that are critical for cytoskeletal integrity and tissue permeability. Together, these results clarify how CDX2 dose-dependently regulates gene expression in the extraembryonic mesoderm and reveal pathways that may underlie the defects in vascular development and allantoic elongation seen in vivo.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Dosage / Gene Regulatory Networks / Induced Pluripotent Stem Cells / CDX2 Transcription Factor Limits: Humans Language: En Journal: Biol Open Year: 2024 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Dosage / Gene Regulatory Networks / Induced Pluripotent Stem Cells / CDX2 Transcription Factor Limits: Humans Language: En Journal: Biol Open Year: 2024 Document type: Article Affiliation country: Estados Unidos