Bach1 regulates self-renewal and impedes mesendodermal differentiation of human embryonic stem cells

Wei, Xiangxiang; Guo, Jr-Hung; Li, Qinhan; Jia, Qianqian; Jing, Qing; Li, Yan; Zhou, Bin; Chen, Jiayu; Gao, Shaorong; Zhang, Xinyue; Jia, Minghan; Niu, Cong; Yang, Wenlong; Zhi, Xiuling; Wang, Xinhong; Yu, Dian; Bai, Lufeng; Wang, Lin; Na, Jie; Zou, Yunzeng; Zhang, Jianyi; Zhang, Shuning; Meng, Dan

doi:10.1126/sciadv.aau7887

Cited by 53 publications

(64 citation statements)

References 45 publications

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“…Furthermore, the increased CSC-like properties induced by CIH were repressed by Bach1 knockdown. Though the effects of Bach1 on maintaining CSC-like property were little reported, our observation is consistent with previous reports that Bach1 can regulate self-renewal and stabilize Nanog, SOX2, and Oct4 in human embryonic stem cells [ 36 ]. Additionally, our previous study found that Bach1 can promote lung CSC phenotype by inducing CD44 expression (have not been published).…”

Section: Discussionsupporting

confidence: 92%

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

et al. 2021

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Background An adverse role for obstructive sleep apnea (OSA) in cancer aggressiveness and mortality has recently emerged from clinical and animal studies, and the reasons have not been fully determined. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis. So far, the relationship between OSA and lung CSCs has not been explored. Method In the present study, we established an orthotopic mouse model of primary lung cancer and utilized chronic intermittent hypoxia (CIH) exposure to mimic OSA status. Results We observed that CIH endows lung cancer with greater metastatic potential, evidenced by increased tumor growth, tumor seeding, and upregulated CSC-related gene expression in the lungs. Notably, the transcription factor BTB and CNC homology 1 (Bach1), a key factor in responding to conditions of oxidative stress, is increased in lung cancer after CIH exposure in vitro and in vivo. Meanwhile, exposing lung cancer cells to CIH promoted cell proliferation, clonal diversity, induced stem-like cell marker expression, and gave rise to CSCs at a relatively higher frequency. Furthermore, the increase of mitochondrial ROS (mtROS) and CSC-marker expression induced by CIH exposure was abolished in Bach1 shRNA-treated lung cancer cells. Conclusions Our results indicated that CIH promoted lung CSC-like properties by activating mtROS, which was partially mediated by Bach1.

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Section: Discussionsupporting

confidence: 92%

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

et al. 2021

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“…In addition to Smad3, Smad2 protein was also increased in Bach1 -deficient, injured muscle. Since Bach1 directly represses the expression of Nodal gene which encodes one of the ligands for the Smad pathway in human embryonic stem cells [ 42 ], Bach1 may regulate Smad pathway at multiple steps. Consistent with the previous report that Smad2 and Smad3 inhibit MyoD and myogenin expression [ 39 ], the expression of the two myogenic transcription factors was reduced in C2C12 cells upon knockdown of Bach1.…”

Section: Discussionmentioning

confidence: 99%

Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation

et al. 2020

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It has been reported that Bach1 -deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that Bach1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of Bach1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by Bach1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in Bach1 -deficient mice and Bach1 -silenced C2C12 cells. Therefore, Bach1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.

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“…In addition, DUB recruitment to substrates via adapter proteins can also be utilized to stabilize transcription factors. This is exemplified by USP7, which has recently been shown to be targeted to stemness factors SOX2, NANOG, and OCT4 via BACH1 to counteract their degradative ubiquitylation, thus ensuring hESC self-renewal [ 110 ]. Taken together, various mechanisms control the dynamic localization of DUBs to enable spatial restriction of ubiquitin signaling during development.…”

Section: Regulatory Principles Impinging On Dubsmentioning

confidence: 99%

“…This was proposed to stabilize these proteins and promote their function in the context of the PRC1 complex to repress the expression of pluripotency genes, ensuring faithful lineage commitment. In addition, recent reports have shown that both, USP21 and USP7 counteract degradative ubiquitylation of NANOG to ensure self-renewal of ESCs [ 110 , 143 ]. This example showcases how several DUBs can target the same transcription factor and it will be interesting to further explore how such interplay regulates ESC maintenance (e.g., through targeting differently localized pools of NANOG).…”

Section: Mechanisms How Dubs Control Developmentmentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

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Bach1 regulates self-renewal and impedes mesendodermal differentiation of human embryonic stem cells

Cited by 53 publications

References 45 publications

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

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