iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes
<p dir="ltr">Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown....
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , |
| منشور في: |
2023
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| الموضوعات: | |
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| _version_ | 1864513533542137856 |
|---|---|
| author | Noura Aldous (15429873) |
| author2 | Ahmed K. Elsayed (13275302) Nehad M. Alajez (7397276) Essam M. Abdelalim (5768072) |
| author2_role | author author author |
| author_facet | Noura Aldous (15429873) Ahmed K. Elsayed (13275302) Nehad M. Alajez (7397276) Essam M. Abdelalim (5768072) |
| author_role | author |
| dc.creator.none.fl_str_mv | Noura Aldous (15429873) Ahmed K. Elsayed (13275302) Nehad M. Alajez (7397276) Essam M. Abdelalim (5768072) |
| dc.date.none.fl_str_mv | 2023-02-07T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1007/s12015-023-10515-3 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/iPSC-Derived_Pancreatic_Progenitors_Lacking_FOXA2_Reveal_Alterations_in_miRNA_Expression_Targeting_Key_Pancreatic_Genes/24935139 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Cardiovascular medicine and haematology Pancreatic development Endocrine pancreas Transcription factors β-cells miRNA-seq RNA-Seq |
| dc.title.none.fl_str_mv | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown. Here, we aimed to capture the dysregulated miRNAs and to identify their pancreatic-specific gene targets in pancreatic progenitors (PPs) derived from wild-type induced pluripotent stem cells (WT-iPSCs) and from iPSCs lacking FOXA2 (FOXA2<sup>–</sup>/<sup>–</sup>iPSCs). To identify differentially expressed miRNAs (DEmiRs), and genes (DEGs), two differentFOXA2<sup>–</sup>/<sup>–</sup>iPSC lines were differentiated into PPs.FOXA2<sup>–</sup>/<sup>–</sup>PPs showed a significant reduction in the expression of the main PP transcription factors (TFs) in comparison to WT-PPs. RNA sequencing analysis demonstrated significant reduction in the mRNA expression of genes involved in the development and function of exocrine and endocrine pancreas. Furthermore, miRNA profiling identified 107 downregulated and 111 upregulated DEmiRs inFOXA2<sup>–</sup>/<sup>–</sup>PPs compared to WT-PPs. Target prediction analysis between DEmiRs and DEGs identified 92 upregulated miRNAs, predicted to target 1498 downregulated genes inFOXA2<sup>–</sup>/<sup>–</sup>PPs. Several important pancreatic TFs essential for pancreatic development were targeted by multiple DEmiRs. Selected DEmiRs and DEGs were further validated using RT-qPCR. Our findings revealed that FOXA2 expression is crucial for pancreatic development through regulating the expression of pancreatic endocrine and exocrine genes targeted by a set of miRNAs at the pancreatic progenitor stage. These data provide novel insights of the effect of FOXA2 deficiency on miRNA-mRNA regulatory networks controlling pancreatic development and differentiation.</p><p><br></p><p dir="ltr">Graphical Abstract</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Stem Cell Reviews and Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1007/s12015-023-10515-3" target="_blank">https://dx.doi.org/10.1007/s12015-023-10515-3</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_5f690b45af6300538a369d6da0a6f974 |
| identifier_str_mv | 10.1007/s12015-023-10515-3 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/24935139 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic GenesNoura Aldous (15429873)Ahmed K. Elsayed (13275302)Nehad M. Alajez (7397276)Essam M. Abdelalim (5768072)Biomedical and clinical sciencesCardiovascular medicine and haematologyPancreatic developmentEndocrine pancreasTranscription factorsβ-cellsmiRNA-seqRNA-Seq<p dir="ltr">Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown. Here, we aimed to capture the dysregulated miRNAs and to identify their pancreatic-specific gene targets in pancreatic progenitors (PPs) derived from wild-type induced pluripotent stem cells (WT-iPSCs) and from iPSCs lacking FOXA2 (FOXA2<sup>–</sup>/<sup>–</sup>iPSCs). To identify differentially expressed miRNAs (DEmiRs), and genes (DEGs), two differentFOXA2<sup>–</sup>/<sup>–</sup>iPSC lines were differentiated into PPs.FOXA2<sup>–</sup>/<sup>–</sup>PPs showed a significant reduction in the expression of the main PP transcription factors (TFs) in comparison to WT-PPs. RNA sequencing analysis demonstrated significant reduction in the mRNA expression of genes involved in the development and function of exocrine and endocrine pancreas. Furthermore, miRNA profiling identified 107 downregulated and 111 upregulated DEmiRs inFOXA2<sup>–</sup>/<sup>–</sup>PPs compared to WT-PPs. Target prediction analysis between DEmiRs and DEGs identified 92 upregulated miRNAs, predicted to target 1498 downregulated genes inFOXA2<sup>–</sup>/<sup>–</sup>PPs. Several important pancreatic TFs essential for pancreatic development were targeted by multiple DEmiRs. Selected DEmiRs and DEGs were further validated using RT-qPCR. Our findings revealed that FOXA2 expression is crucial for pancreatic development through regulating the expression of pancreatic endocrine and exocrine genes targeted by a set of miRNAs at the pancreatic progenitor stage. These data provide novel insights of the effect of FOXA2 deficiency on miRNA-mRNA regulatory networks controlling pancreatic development and differentiation.</p><p><br></p><p dir="ltr">Graphical Abstract</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Stem Cell Reviews and Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1007/s12015-023-10515-3" target="_blank">https://dx.doi.org/10.1007/s12015-023-10515-3</a></p>2023-02-07T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1007/s12015-023-10515-3https://figshare.com/articles/journal_contribution/iPSC-Derived_Pancreatic_Progenitors_Lacking_FOXA2_Reveal_Alterations_in_miRNA_Expression_Targeting_Key_Pancreatic_Genes/24935139CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/249351392023-02-07T03:00:00Z |
| spellingShingle | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes Noura Aldous (15429873) Biomedical and clinical sciences Cardiovascular medicine and haematology Pancreatic development Endocrine pancreas Transcription factors β-cells miRNA-seq RNA-Seq |
| status_str | publishedVersion |
| title | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| title_full | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| title_fullStr | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| title_full_unstemmed | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| title_short | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| title_sort | iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes |
| topic | Biomedical and clinical sciences Cardiovascular medicine and haematology Pancreatic development Endocrine pancreas Transcription factors β-cells miRNA-seq RNA-Seq |