| Autor: |
Tomohiro Nishino, Sanjeev S. Ranade, Angelo Pelonero, Benjamin J. van Soldt, Lin Ye, Michael Alexanian, Frances Koback, Yu Huang, Nandhini Sadagopan, Arun Padmanabhan, Reuben Thomas, Joke G. van Bemmel, Casey A. Gifford, Mauro W. Costa, Deepak Srivastava |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.07.25.501463 |
| Popis: |
Birth defects occur in ∼6% of all live births and can be caused by combinations of genetic and environmental influences1. Large-scale DNA sequencing efforts are revealing genetic influences2,3, but investigations into the contributions of environmental factors have largely been limited to association studies with limited mechanistic insight. Hyperglycemia present in pre-gestational diabetic mothers is among the most frequent environmental contributor to congenital defects and results in an increased incidence of congenital heart defects and craniofacial anomalies4. However, the cell types involved and underlying mechanisms by which maternal hyperglycemia affects these regions are unknown. Here, we utilized multi-modal single cell analyses to reveal that maternal diabetes affects the epigenomic and transcriptomic state of specific subsets of cardiac and craniofacial progenitors during embryogenesis. A previously unrecognized subpopulation of anterior heart field progenitors expressing Alx3 acquired a more posterior identity in response to maternal hyperglycemia, based on gene expression and chromatin status. Similarly, a sub-population of neural crest-derived cells in the second pharyngeal arch, which contributes to craniofacial structures, also displayed abnormalities in cell specification and patterning. Analysis of differentially accessible chromatin regions demonstrated that disrupted patterning was associated with increased intrinsic retinoic acid signaling in affected cell types in response to maternal diabetes and hyperglycemia. This work demonstrates how an environmental insult can have highly selective epigenomic consequences on discrete cell types leading to developmental patterning defects. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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