Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains

Shao, Zhicheng; Yao, Chunping; Khodadadi‐Jamayran, Alireza; Xu, Weihua; Townes, Tim M.; Crowley, Michael R.; Hu, Kejin

doi:10.1016/j.celrep.2016.08.060

Cited by 29 publications

(36 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, our results showed that JQ1 caused the loss of cellular extensions in NDs, followed by rounding of cells. These results are similar to previously reported morphological changes observed with other JQ1 sensitive cells, including pancreatic stellate cells and human foreskin fibroblasts [ 40 , 41 ].…”

Section: Discussionsupporting

confidence: 92%

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells

et al. 2018

View full text Add to dashboard Cite

Bromodomain and extra-terminal domain (BET) proteins regulate the transcription of many genes including c-MYC, a proto-oncogene, which is upregulated in many types of cancers. The thienodiazepine class of BET inhibitors, such as JQ1, inhibits growth of cancer cells and triggers apoptosis. However, the effects of BET inhibitors on normal cells and mesenchymal stem cells (MSCs), which are important in routine maintenance or regeneration of damaged cells and tissues, are poorly investigated. Previously, we have shown that JQ1 causes human umbilical cord MSCs to undergo cell cycle arrest and neural differentiation. In this study, we determined that JQ1 is more deleterious to neuronal derivatives (NDs) than adipogenic, chondrogenic or osteogenic derivatives of MSCs. NDs treated with JQ1 showed a significant decrease in cell proliferation, viability, and neuronal markers. JQ1 caused cell death through the intrinsic apoptotic pathway in NDs as determined by activation of Caspase 9 and increased expression of Cytochrome C. A comparative analysis showed differential action of JQ1 on MSCs and NDs. The results showed selective neuronal toxicity of JQ1 in NDs but not in the undifferentiated MSCs. These findings suggest a more careful examination of the selection and use of BET inhibitors as therapeutic agents, as they may cause unwanted damage to non-target cells and tissues.

show abstract

Section: Discussionsupporting

confidence: 92%

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In an effort to improve the efficiency of this process, we screened a collection of seven chemical compounds that were previously shown to promote reprogramming of fibroblasts to induced pluripotent stem cells (Table S1) (Brady et al., 2013, Dutta et al., 2011, Esteban et al., 2010, Ichida et al., 2014, Li et al., 2012, Maherali and Hochedlinger, 2009, Shao et al., 2016). Mouse embryonic fibroblasts (MEFs) were isolated from transgenic mice that express GFP under the control of the cardiac α-myosin heavy chain promoter (αMHC-GFP), and reprogramming was induced by transducing the cells with retroviruses encoding for GHMT.…”

Section: Resultsmentioning

confidence: 99%

Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity

et al. 2017

View full text Add to dashboard Cite

SummaryConversion of fibroblasts into functional cardiomyocytes represents a potential means of restoring cardiac function after myocardial infarction, but so far this process remains inefficient and little is known about its molecular mechanisms. Here we show that DAPT, a classical Notch inhibitor, enhances the conversion of mouse fibroblasts into induced cardiac-like myocytes by the transcription factors GATA4, HAND2, MEF2C, and TBX5. DAPT cooperates with AKT kinase to further augment this process, resulting in up to 70% conversion efficiency. Moreover, DAPT promotes the acquisition of specific cardiomyocyte features, substantially increasing calcium flux, sarcomere structure, and the number of spontaneously beating cells. Transcriptome analysis shows that DAPT induces genetic programs related to muscle development, differentiation, and excitation-contraction coupling. Mechanistically, DAPT increases binding of the transcription factor MEF2C to the promoter regions of cardiac structural genes. These findings provide mechanistic insights into the reprogramming process and may have important implications for cardiac regeneration therapies.

show abstract

“…We used two types of cutoffs for DESeq2 read counts for genes considered expressed, mean read count and individual read count cutoff. In DESeq2 normalization, we previously used a mean normalized read counts of 50 for the cell type in question as a cutoff for a gene to be considered active [7,8]. This cutoff is supported by our current data (table S1).…”

Section: Read Count Cutoff Of Deseq2 Data For Expressed Genementioning

confidence: 56%

“…Conversion of fibroblasts into iPSCs involves dramatic changes in cell morphology and establishes a unique cellular colony characteristic of PSC culture. In fact, high quality iPS cell lines can be established by selecting colonies with the characteristic cell and colony morphology without a reporter [7,8,20], and automatic imaging system can be used for identification of high quality iPSC colonies [21]. GO analyses of reprogramome reveal that 22 and 23 such GO terms are associated with the downreprogramome and upreprogramome, respectively (Table S6).…”

Section: Profiling and Quantification Of Reprogramming In Cell Morphomentioning

confidence: 99%

“…iPSC reprogramming from human fibroblasts is a prolonged and stochastic process with a very low efficiency [4][5][6]. One reason for this inefficient conversion of cell fates is probably the great expanse of reprogramming required [7,8]. Although it is considered to be extensive as well as intensive, the degree of iPSC reprogramming has not been determined quantitatively.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Profiling of the reprogramome and quantification of fibroblast reprogramming to pluripotency

Ianov

Crossman

2020

Preprint

Self Cite

View full text Add to dashboard Cite

Pluripotent state can be established via reprogramming of somatic nuclei by factors within an oocyte or by ectopic expression of a few transgenes. Considered as being extensive and intensive, the full complement of genes to be reprogrammed, however, has never been defined, nor has the degree of reprogramming been determined quantitatively. Here, we propose a new concept of reprogramome, which is defined as the full complement of genes that need to be reprogrammed to the expression levels found in pluripotent stem cells (PSCs). This concept in combination with RNAseq enables us to precisely profile reprogramome and sub-reprogramomes, and study the reprogramming process with the help of other available tools such as GO analyses. With reprogramming of human fibroblasts into PSCs as an example, we have defined the full complement of the human fibroblast-to-PSC reprogramome. Furthermore, our analyses of the reprogramome revealed that WNT pathways and genes with roles in cellular morphogenesis have to be extensively and intensely reprogrammed for the establishment of pluripotency. We further developed the first mathematical model to quantitate the overall reprogramming, as well as reprogramming in a specific cellular feature such as WNT signaling pathways and genes regulating cellular morphogenesis. We anticipate that our concept and mathematical model may be applied to study and quantitate other reprogramming (pluripotency reprogramming from other somatic cells, and lineage reprogramming), as well as transcriptional and epigenetic differences between any two types of cells including cancer cells and their normal counterparts.

show abstract

Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains

Cited by 29 publications

References 39 publications

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells

Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity

Profiling of the reprogramome and quantification of fibroblast reprogramming to pluripotency

Contact Info

Product

Resources

About