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Conference Paper: Hyperglycemia impedes hESC differentiation into definitive endoderm through modulation of histone methylation patterns

TitleHyperglycemia impedes hESC differentiation into definitive endoderm through modulation of histone methylation patterns
Authors
Issue Date2015
PublisherInternational Society For Stem Cell Research.
Citation
The 13th Annual Meeting of the International Society For Stem Cell Research (ISSCR 2015), Stockholm, Sweden, 24-27 June 2015. In Abstract Book, 2015, p. 137, abstract W-1386 How to Cite?
AbstractType 2 Diabetes Mellitus (T2D) is a metabolic syndrome characterized by hyperglycemia and insulin resistance. Fetal exposure to maternal diabetes is a possible cause for T2D, as offsprings of diabetic mothers had higher prevalence of impaired glucose tolerance and T2D at adulthood1. Epigenetic changes could be the underlying mechanism, since the epigenome is vulnerable and susceptible to environment-induced dysregulation during early fetal development2,3. In light of these, we hypothesized that intrauterine hyperglycemic environment led to persistent epigenetic modifications associated with impaired fetal pancreatic differentiation. The human embryonic stem cell line (hESCs), Val3, was selected as in-vitro model in this study, because of its efficiency of differentiation into definitive endoderm (DE), an important intermediate stage along the pancreatic lineage. From our results, we found that the expressions of DE markers (SOX17, FOXA2, CXCR4 and EOMES) were significantly suppressed when induction was done in the presence of high glucose concentration (50mM D-glucose). Upon DE differentiation, the repressive histone methylation mark H3K27me3 initially bound to the promoters of the DE markers in hESCs were lost. Interestingly, these marks were partially retained under hyperglycemic condition (25mM and 50mM). Further investigation into the temporal methylation patterns during DE differentiation revealed the upregulation of H3K27me3 binding on DE markers appeared as early from day 2 onwards upon hyperglycemic treatment. Treatment with adenosine-2’,3’-dialdehyde (Adox), a methyltransferase inhibitor, from day 2 onwards significantly rescued the expression of DE markers and restored normal histone methylation patterns upon hyperglycemic treatment. Our findings was further proved by an in-vivo diabetic mouse model induced by low dose of streptozotocin that embryos at 7.5dpc born to diabetic mothers had lower percentage of Sox17+ Foxa2+ Cxcr4+ cells when compared to control. To conclude, our findings suggested hyperglycemia impeded differentiation of hESCs into DE by affecting the histone methylation patterns. The impairment of DE development by hyperglycemia was observed in a diabetic mouse model.
DescriptionConference Theme: An Unveiling of Stem Cell Innovation
Persistent Identifierhttp://hdl.handle.net/10722/219034

 

DC FieldValueLanguage
dc.contributor.authorChen, CH-
dc.contributor.authorLee, YL-
dc.contributor.authorFong, SW-
dc.contributor.authorYeung, SB-
dc.date.accessioned2015-09-18T07:11:00Z-
dc.date.available2015-09-18T07:11:00Z-
dc.date.issued2015-
dc.identifier.citationThe 13th Annual Meeting of the International Society For Stem Cell Research (ISSCR 2015), Stockholm, Sweden, 24-27 June 2015. In Abstract Book, 2015, p. 137, abstract W-1386-
dc.identifier.urihttp://hdl.handle.net/10722/219034-
dc.descriptionConference Theme: An Unveiling of Stem Cell Innovation-
dc.description.abstractType 2 Diabetes Mellitus (T2D) is a metabolic syndrome characterized by hyperglycemia and insulin resistance. Fetal exposure to maternal diabetes is a possible cause for T2D, as offsprings of diabetic mothers had higher prevalence of impaired glucose tolerance and T2D at adulthood1. Epigenetic changes could be the underlying mechanism, since the epigenome is vulnerable and susceptible to environment-induced dysregulation during early fetal development2,3. In light of these, we hypothesized that intrauterine hyperglycemic environment led to persistent epigenetic modifications associated with impaired fetal pancreatic differentiation. The human embryonic stem cell line (hESCs), Val3, was selected as in-vitro model in this study, because of its efficiency of differentiation into definitive endoderm (DE), an important intermediate stage along the pancreatic lineage. From our results, we found that the expressions of DE markers (SOX17, FOXA2, CXCR4 and EOMES) were significantly suppressed when induction was done in the presence of high glucose concentration (50mM D-glucose). Upon DE differentiation, the repressive histone methylation mark H3K27me3 initially bound to the promoters of the DE markers in hESCs were lost. Interestingly, these marks were partially retained under hyperglycemic condition (25mM and 50mM). Further investigation into the temporal methylation patterns during DE differentiation revealed the upregulation of H3K27me3 binding on DE markers appeared as early from day 2 onwards upon hyperglycemic treatment. Treatment with adenosine-2’,3’-dialdehyde (Adox), a methyltransferase inhibitor, from day 2 onwards significantly rescued the expression of DE markers and restored normal histone methylation patterns upon hyperglycemic treatment. Our findings was further proved by an in-vivo diabetic mouse model induced by low dose of streptozotocin that embryos at 7.5dpc born to diabetic mothers had lower percentage of Sox17+ Foxa2+ Cxcr4+ cells when compared to control. To conclude, our findings suggested hyperglycemia impeded differentiation of hESCs into DE by affecting the histone methylation patterns. The impairment of DE development by hyperglycemia was observed in a diabetic mouse model.-
dc.languageeng-
dc.publisherInternational Society For Stem Cell Research.-
dc.relation.ispartofAnnual Meeting of the International Society For Stem Cell Research, ISSCR 2015-
dc.titleHyperglycemia impedes hESC differentiation into definitive endoderm through modulation of histone methylation patterns-
dc.typeConference_Paper-
dc.identifier.emailLee, YL: cherielee@hku.hk-
dc.identifier.emailFong, SW: szewan11@hku.hk-
dc.identifier.emailYeung, SB: wsbyeung@hku.hk-
dc.identifier.authorityLee, YL=rp00308-
dc.identifier.authorityYeung, SB=rp00331-
dc.identifier.hkuros253011-
dc.identifier.spage137, abstract W-1386-
dc.identifier.epage137, abstract W-1386-
dc.publisher.placeSweden-

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