CBP/p300 inhibitor C646 prevents high glucose exposure induced neuroepithelial cell proliferation

Bai, Baoling; Zhang, Qin; Wan, Chunlei; Li, Dan; Zhang, Ting; Li, Huili

doi:10.1002/bdr2.1360

Cited by 14 publications

(10 citation statements)

References 52 publications

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“…High glucose is a significant risk factor for NTDs. Bai et al have reported that maternal diabetes leads to an increase in H4K5/K8/K12/K16 acetylation levels, and that the CBP selective inhibitor, C646, could efficiently prevent an increase or emergence of histone H4 acetylation and neuroepithelial cell proliferation (Bai et al, 2018). Furthermore, a deletion in the neuronal Nap1l2 (nucleosome assembly protein 1-like 2) gene in mice leads to an increase in acetylated histone H3K9/14 at the Cdkn1c transcription site and causes NTDs (Attia, Rachez, De Pauw, Avner, & Rogner, 2007).…”

Section: Discussionmentioning

confidence: 99%

Identification of histone acetylation markers in human fetal brains and increased H4K5ac expression in neural tube defects

Wan

Bai

et al. 2019

Molec Gen & Gen Med

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BackgroundNeural tube defects (NTDs) are severe common birth defects that result from a failure in neural tube closure (NTC). Our previous study has shown that decreased histone methylation altered the regulation of genes linked to NTC. However, the effect of alterations in histone acetylation in human fetuses with NTDs, which are another functional posttranslation modification, remains elusive. Thus, we aimed to identify acetylation sites and changes in histone in patients with NTDs.MethodsFirst, we identified histone acetylation sites between control human embryonic brain tissue and NTDs using Nano‐HPLC‐MS/MS. Next, we evaluated the level of histone acetylation both groups via western blotting (WB). Finally, we used LC‐ESI‐MS and WB to compare whether histone H4 acetylation was different in NTDs.ResultsA total of 43 histone acetylation sites were identified in human embryonic brain tissue, which included 16 novel sites. Furthermore, we found an increased histone acetylation and H4K5ac in tissue with NTDs.ConclusionOur result present a comprehensive map of histone H4 modifications in the human fetal brain. Furthermore, we provide experimental evidence supporting a relationship between histone H4K5ac and NTDs. This offers a new insight into the pathological role of histone modifications in human NTDs.

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Section: Discussionmentioning

confidence: 99%

Identification of histone acetylation markers in human fetal brains and increased H4K5ac expression in neural tube defects

Wan

Bai

et al. 2019

Molec Gen & Gen Med

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“…As described in our previous paper (Bai et al., 2018), diabetes was induced in 7‐ to 9‐week‐old virgin female FVB mice by two intraperitoneal injections of 100 mg/kg body weight streptozotocin (STZ; CAS18883‐66‐4, Sigma) in 100 mM sodium citrate buffer at pH 4.5 performed at an interval of 1 week. After fasting for 12 hr, 11 dams were confirmed as having diabetes when the blood glucose level exceeded 14 mM (250 mg/dl) after STZ treatment.…”

Section: Methodsmentioning

confidence: 99%

Identification of histone malonylation in the human fetal brain and implications for diabetes‐induced neural tube defects

Zhang

Cai

Xiao

et al. 2020

Molec Gen & Gen Med

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Background Neural tube defects (NTDs) are severe congenital malformations. Diabetes during pregnancy is a risk factor for NTDs, but its mechanism remains elusive. Emerging evidence suggests that protein malonylation is involved in diabetes. Here, we report the correlation between histone lysine malonylation in diabetes‐induced NTDs. Methods Nano‐HPLC/MS/MS was used to screen the histone malonylation profile in human embryonic brain tissue. Then, the histone malonylation level was compared between the brains of normal control mice and mice with diabetes‐induced NTDs. Finally, the histone malonylation level was compared under high glucose exposure in an E9 neuroepithelial cell line (NE4C). Results A total of 30 histone malonylation sites were identified in human embryonic brain tissue, including 18 novel sites. Furthermore, we found an increased histone malonylation level in brain tissues from mice with diabetes‐induced NTDs. Finally, both the histone malonylation modified sites and the modified levels were proved to be increased in the NE4C treated with high glucose. Conclusion Our results present a comprehensive map of histone malonylation in the human fetal brain. Furthermore, we provide experimental evidence supporting a relationship between histone malonylation and NTDs caused by high glucose‐induced diabetes. These findings offer new insights into the pathological role of histone modifications in human NTDs.

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“…Although DMSO has these defined properties for cellular differentiation, its effect on direct cardiac reprogramming has never been reported. cAMP response element-binding protein (CREB) binding protein (also called CBP or KAT3A) and adenoviral E1A binding protein p300 (also called p300 or KAT3B) are two homologues of transcriptional coactivators which play important roles in many biological processes, including proliferation [25], differentiation [26] and apoptosis [27]. Both CBP and p300 have similar protein structures, consisting of five protein interaction domains: the nuclear receptor interaction (RID) domain, kinase-inducible (KIX) domain, cysteine/histidine region (TAZ1/CH1 and TAZ2/CH2) and interferon response binding domain (IBiD).…”

Section: Introductionmentioning

confidence: 99%

Dimethyl sulfoxide (DMSO) enhances direct cardiac reprogramming by inhibiting the bromodomain of coactivators CBP/p300

Lim

Motakis

Tan

et al. 2021

Journal of Molecular and Cellular Cardiology

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Direct cardiac reprogramming represents an attractive way to reversing heart damage caused by myocardial infarction because it removes fibroblasts, while also generating new functional cardiomyocytes. Yet, the main hurdle for bringing this technique to the clinic is the lack of efficacy with current reprogramming protocols. Here, we describe our unexpected discovery that DMSO is capable of significantly augmenting direct cardiac reprogramming in vitro. Methods and results: Upon induction with cardiac transcription factors-Gata4, Hand2, Mef2c and Tbx5 (GHMT), the treatment of mouse embryonic fibroblasts (MEFs) with 1% DMSO induced ~5 fold increase in Myh6-mCherry+ cells, and significantly upregulated global expression of cardiac genes, including Myh6, Ttn, Nppa, Myh7 and Ryr2. RNA-seq confirmed upregulation of cardiac gene programmes and downregulation of extracellular matrix-related genes. Treatment of TGF-β1, DMSO, or SB431542, and the combination thereof, revealed that DMSO most likely targets a separate but parallel pathway other than TGF-β signalling. Subsequent experiments using small molecule screening revealed that DMSO enhances direct cardiac reprogramming through inhibition of the CBP/p300 bromodomain, and not its acetyltransferase property. Conclusion:In conclusion, our work points to a direct molecular target of DMSO, which can be used for augmenting GHMT-induced direct cardiac reprogramming and possibly other cell fate conversion processes.Non-standard abbreviations and acronyms: αMHC, Alpha myosin heavy chain; BET, Bromodomain and extra-terminal; CBP/p300, cAMP response element-binding protein (CREB) binding protein/ adenoviral E1A binding protein p300;

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CBP/p300 inhibitor C646 prevents high glucose exposure induced neuroepithelial cell proliferation

Abstract: Our data provide complementary insights for potential mechanisms of maternal diabetes induced NTDs.

Cited by 14 publications

References 52 publications

Identification of histone acetylation markers in human fetal brains and increased H4K5ac expression in neural tube defects

Identification of histone acetylation markers in human fetal brains and increased H4K5ac expression in neural tube defects

Identification of histone malonylation in the human fetal brain and implications for diabetes‐induced neural tube defects

Dimethyl sulfoxide (DMSO) enhances direct cardiac reprogramming by inhibiting the bromodomain of coactivators CBP/p300

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