Sirtuin inhibitor Ex‐527 causes neural tube defects, ventral edema formations, and gastrointestinal malformations in <i><scp>X</scp>enopus laevis</i> embryos

Ohata, Yoshihisa; Matsukawa, Shinya; Moriyama, Yuki; Michiue, Tatsuo; Morimoto, Kenta; Sato, Yuka; Kuroda, Hiroki

doi:10.1111/dgd.12145

Cited by 14 publications

(11 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, Sirt1 is expressed in axonal growth cone wherein it regulates formation and elongation of axons (Li et al, 2013 ). Studies have shown that Sirt1 knockdown results in neural defects such as exencephaly in mice (Cheng et al, 2003 ; McBurney et al, 2003 ) and NTDs in Xenopus embryos (Ohata et al, 2014 ), suggesting the importance of Sirt1 in neural tube formation. In addition, Sirt1 is known to regulate memory and plasticity (Gao et al, 2010 ) and is required for normal cognitive function (Michan et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Maternal Diabetes Alters Expression of MicroRNAs that Regulate Genes Critical for Neural Tube Development

Ramya

Sudhaharan

Bay

et al. 2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Maternal diabetes is known to cause neural tube defects (NTDs) in embryos and neuropsychological deficits in infants. Several metabolic pathways and a plethora of genes have been identified to be deregulated in developing brain of embryos by maternal diabetes, although the exact mechanism remains unknown. Recently, miRNAs have been shown to regulate genes involved in brain development and maturation. Therefore, we hypothesized that maternal diabetes alters the expression of miRNAs that regulate genes involved in biological pathways critical for neural tube development and closure during embryogenesis. To address this, high throughput miRNA expression profiling in neural stem cells (NSCs) isolated from the forebrain of embryos from normal or streptozotocin-induced diabetic pregnancy was carried out. It is known that maternal diabetes results in fetal hypoglycemia/hyperglycemia or hypoxia. Hence, NSCs from embryos of control pregnant mice were exposed to low or high glucose or hypoxia in vitro. miRNA pathway analysis revealed distinct deregulation of several biological pathways, including axon guidance pathway, which are critical for brain development in NSCs exposed to different treatments. Among the differentially expressed miRNAs, the miRNA-30 family members which are predicted to target genes involved in brain development was upregulated in NSCs from embryos of diabetic pregnancy when compared to control. miRNA-30b was found to be upregulated while its target gene Sirtuin 1 (Sirt1), as revealed by luciferase assay, was down regulated in NSCs from embryos of diabetic pregnancy. Further, overexpression of miRNA-30b in NSCs, resulted in decreased expression of Sirt1 protein, and altered the neuron/glia ratio. On the other hand, siRNA mediated knockdown of Sirt1 in NSCs promoted astrogenesis, indicating that miRNA-30b alters lineage specification via Sirt1. Overall, these results suggest that maternal diabetes alters the genes involved in neural tube formation via regulating miRNAs.

show abstract

Section: Discussionmentioning

confidence: 99%

Maternal Diabetes Alters Expression of MicroRNAs that Regulate Genes Critical for Neural Tube Development

Ramya

Sudhaharan

Bay

et al. 2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Together these HDAC inhibitors can inhibit a majority of the histone deacetylases 17 28 . TSA is an inhibitor for class I and II histone deacetylases, NAM is an inhibitor for class III histone deacetylases and EX-527 is a widely used inhibitor of sirtuin enzymes 33 34 . In a future study, we will identify which HDAC inhibitor is responsible for the observed effects.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1

Nie

Gao

et al. 2015

Sci Rep

View full text Add to dashboard Cite

T helper 17 (Th17) cells not only play critical roles in protecting against bacterial and fungal infections but are also involved in the pathogenesis of autoimmune diseases. The retinoic acid-related orphan receptor (RORγt) is a key transcription factor involved in Th17 cell differentiation through direct transcriptional activation of interleukin 17(A) (IL-17). How RORγt itself is regulated remains unclear. Here, we report that p300, which has histone acetyltransferase (HAT) activity, interacts with and acetylates RORγt at its K81 residue. Knockdown of p300 downregulates RORγt protein and RORγt-mediated gene expression in Th17 cells. In addition, p300 can promote RORγt-mediated transcriptional activation. Interestingly, the histone deacetylase (HDAC) HDAC1 can also interact with RORγt and reduce its acetylation level. In summary, our data reveal previously unappreciated posttranslational regulation of RORγt, uncovering the underlying mechanism by which the histone acetyltransferase p300 and the histone deacetylase HDAC1 reciprocally regulate the RORγt-mediated transcriptional activation of IL-17.

show abstract

“…In addition, EX-527 treatment leads to an increase in levels of acetylated p53 in cells subjected to genotoxic agents 35 . It has been also shown that EX-527 adversely affects early developmental events of vertebrate embryos 36 . Interestingly, EX-527 suppresses deacetylation of mutant huntingtin protein and thus promotes degradation of the acetylated mutant by autophagy 37 .…”

mentioning

confidence: 99%

A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons

Kim

Lee

Chang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Sirtuin 1 (SIRT1) is known to suppress differentiation of pluripotent/multipotent cells and neural progenitor cells into neurons by blocking activation of transcription factors critical for neurogenesis. EX-527 is a highly selective and potent inhibitor against SIRT1 and has been used as a chemical probe that modulates SIRT1-associated biological processes. However, the effect of EX-527 on neuronal differentiation in pluripotent cells has not been well elucidated. Here, we report an examination of EX-527 effects on neurogenesis of pluripotent P19 cells. The results showed that EX-527 greatly accelerated differentiation of P19 cells into neurons without generation of cardiac cells and astrocytes. Importantly, neurons derived from P19 cells treated with EX-527 generated voltage-dependent sodium currents and depolarization-induced action potentials. The findings indicate that the differentiated cells have electrophysiological properties. The present study suggests that the selective SIRT1 inhibitor could have the potential of being employed as a chemical inducer to generate functionally active neurons.

show abstract

Sirtuin inhibitor Ex‐527 causes neural tube defects, ventral edema formations, and gastrointestinal malformations in Xenopus laevis embryos

Cited by 14 publications

References 44 publications

Maternal Diabetes Alters Expression of MicroRNAs that Regulate Genes Critical for Neural Tube Development

Maternal Diabetes Alters Expression of MicroRNAs that Regulate Genes Critical for Neural Tube Development

Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1

A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons

Contact Info

Product

Resources

About