Selective targeting of TET catalytic domain promotes somatic cell reprogramming

Singh, Anup K.; Zhao, Bo; Li, Xiuhua; Wang, Xin; Zhang, Lipeng; Qin, Hanjun; Wu, Xiwei; Ma, Yuelong; Horne, David; Yu, Xiaochun

doi:10.1073/pnas.1910702117

“…However, there are several reports indicating that TET1 may function as an oncogene by mediating hypomethylation upon targeting by partner proteins in different cancers [27,40]. Recent study showed that TET1 protein can interact with speci c partners and play a biological role through its catalytic and noncatalytic domains [41]. We speculated that the possible explanation for the distinct roles of TET1 is different upstream regulation factors in speci c status and different interacting partners in speci c cell type.…”

Section: Discussionmentioning

confidence: 91%

Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis

Chen

¹

,

Chen

²

,

Li

³

et al. 2021

Environmental Pollution

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“…However, their roles in FLS and RA progression are not known. ID proteins are targets of the BMP signaling 32 , and BMP-SMAD-ID signaling network was previously reported to play a role in tumor growth and angiogenesis [33][34][35] . Interestingly, the BMP-SMAD-ID axis was reported to suppress p16/INK4A-mediated cell senescence during the reprogramming of fibroblasts into pluripotent stem cells 36 .…”

Section: Discussionmentioning

confidence: 99%

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Gangishetti

¹

,

Ramírez-Pérez

²

,

Jones

³

et al. 2020

Sci Rep

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Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.

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“…However, their roles in FLS and RA progression are not known. ID proteins are targets of the BMP signaling (31), and BMP-SMAD-ID signaling network was previously reported to play a role in tumor growth and angiogenesis (32)(33)(34). Interestingly, the BMP-SMAD-ID axis was reported to suppress p16/INK4A-mediated cell senescence during the reprogramming of fibroblasts into pluripotent stem cells (35).…”

Section: Discussionmentioning

confidence: 99%

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Gangishetti

¹

,

Ramírez-Pérez

²

,

Jones

³

et al. 2020

Preprint

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Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established proinflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence. on a Hi-Seq 2500 System (University of Georgia Genomics Core) to generate data in FastQ file format. In order to study chromatin accessibility changes due to chronic inflammation, we downloaded FastQ files from a DNase I hypersensitivity sequencing (DNase-seq) experiment of wild-type FLS and inflamed FLS from inflammatory arthritis mouse model (Table S1). FastQ files from the ATAC-seq and DNase-seq experiments were analyzed using the Strand NGS sequence analysis pipeline first by aligning the sequences to the mouse genome, mm10 build, followed by removal of duplicate reads.Peak calling and gene annotation were performed by MACS2 algorithm using a padding distance of 5 kb from the transcription start sites of genes. Pathway analysis. Ingenuity Pathway Analysis tool was used to predict the canonical regulatory pathways and diseases and functions associated with the SAGs and SRGs (38). Functional protein-protein analysis was performed using STRING protein-protein interaction plugin on Cytoscape, an open source software platform for visualizing complex networks pathway analysis tool (39, 40). Open-source tool, ChEA3 that uses ChIP-seq experiments from the ENCODE database was used to predict transcription factors associations with SAG and SRGs (17).

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Selective targeting of TET catalytic domain promotes somatic cell reprogramming

Cited by 49 publications

References 30 publications

Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis

Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

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