Super-enhancers conserved within placental mammals maintain stem cell pluripotency

Zhang, Juqing; Zhou, Yuwen; Y, Wei; Zhu, Zhenshuo; Wu, Xiaolong; Yu, Shuai; Shen, Qiaoyan; Pan, Qin; Xu, Wenjing; Zhang, Rui; Wu, Xue-Ru; Li, Xinmei; Li, Yayu; Li, Yunxiang; Wang, Yu; Peng, Sha; Zhang, Shiqiang; Lei, Anmin; Ding, Xinbao; Yang, Fan; Chen, Xingqi; Li, Na; Liao, Mingzhi; Wang, Wei; Hua, Jinlian

doi:10.1073/pnas.2204716119

Cited by 16 publications

(15 citation statements)

References 85 publications

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“…Consistent with previous reports, genes involved in cell cycle such as E2F targets and G2M checkpoint were significantly downregulated in ABE-treated cells [ 44 ]. Meanwhile, JQ1-treated cells showed a dysfunction of epigenetic regulation [ 45 ]. Notably, compared with either monotherapy, the combination of ABE and JQ1 induced a significantly more severe suppression of cell cycle, which was accordant at both time points (Fig.…”

Section: Resultsmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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Section: Resultsmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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“…Super-enhancers have been found to be important for normal developmental processes, and have been implicated as drivers of disease due to enrichment of disease-associated genetic variation (Hnisz et al, 2013). We believe that the importance of super-enhancer function across development is underscored by their characteristic evolutionary conservation in vertebrates (Zhang et al, 2022, (Khan et al, 2018, (Pérez-Rico et al, 2017). That is, genomic sequences within SEs have remained largely consistent over time, perhaps because they are critical for proper organogenesis and thus continued survival.…”

Section: Discussionmentioning

confidence: 99%

Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development

Honnell,

Sweeney,

Norrie

et al. 2023

Preprint

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Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory transcription factor Vsx2 in a developmental stage- and cell-type specific manner. The Vsx2 SE is evolutionarily conserved in vertebrates, suggesting that these modules are important for retinal development across species. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.

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“…Confocal Laser Microscope Setup (TCS SP8 SR, Leica) was used to capture the images, which were then processed using LAS AF Lite (Leica). 23…”

Section: Tissue and Organoid Immunofluorescence Stainingmentioning

confidence: 99%

Induction of lung progenitor cell‐like organoids by porcine pluripotent stem cells

Yang,

Wu,

Wang

et al. 2024

The FASEB Journal

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Organoids are in vitro 3D models that are generated using stem cells to study organ development and regeneration. Despite the extensive research on lung organoids, there is limited information on pig lung cell generation or development. Here, we identified five epithelial cell types along with their characteristic markers using scRNA‐seq. Additionally, we found that NKX2.1 and FOXA2 acted as the crucial core transcription factors in porcine lung development. The presence of SOX9/SOX2 double‐positive cells was identified as a key marker for lung progenitor cells. The Monocle algorithm was used to create a pseudo‐temporal differentiation trajectory of epithelial cells, leading to the identification of signaling pathways related to porcine lung development. Moreover, we established the differentiation method from porcine pluripotent stem cells (pPSCs) to SOX17+FOXA2+ definitive endoderm (DE) and NKX2.1+FOXA2+CDX2− anterior foregut endoderm (AFE). The AFE is further differentiated into lung organoids while closely monitoring the differentiation process. We showed that NKX2.1 overexpression facilitated the induction of lung organoids and supported subsequent lung differentiation and maturation. This model offers valuable insights into studying the interaction patterns between cells and the signaling pathways during the development of the porcine lung.

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Super-enhancers conserved within placental mammals maintain stem cell pluripotency

Cited by 16 publications

References 85 publications

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development

Induction of lung progenitor cell‐like organoids by porcine pluripotent stem cells

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