Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3

Wang, Saifeng; Chim, Bryan; Su, Yijun; Khil, Pavel P.; Wong, May Q.; Wang, Xiantao; Foroushani, Amir; Smith, Patrick; Liu, Xiuhuai; Li, Rui; Ganesan, Sundar; Kanellopoulou, Chrysi; Hafner, Markus; Muljo, Stefan A.

doi:10.1101/gad.325100.119

Cited by 58 publications

(57 citation statements)

References 82 publications

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“…Interestingly, as mentioned above, we identified strong binding of RBM4 to its own mRNA, specifically at exon 3 ( Fig. S3A) which suggest the possibility of auto-regulation reminiscent of master regulators such as LIN28B (45)(46)(47). Previously, we discovered that RBM4 regulated ULBP1 via alternative splicing (32).…”

Section: Resultssupporting

confidence: 64%

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Foroushani

Chim

Wong

et al. 2020

Preprint

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The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts (Gerstberger et al., 2014). Most studies of RBPs concentrate on their action on mRNAs that encode protein, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements termed endogenous retroviruses (ERVs) that comprise ~8% of the human genome. Some ERVs have been shown to be transcribed under physiological and pathological conditions suggesting that sophisticated regulatory mechanisms to coordinate and prevent their ectopic expression exist. However, it is unknown whether RBPs and ERV transcripts directly interact to provide a post-transcriptional layer of regulation. Here, we implemented a computational pipeline to determine the correlation of expression between individual RBPs and ERVs from single-cell or bulk RNA sequencing data. One of our top candidates for an RBP negatively regulating ERV expression was RNA-Binding Motif Protein 4 (RBM4). We used PAR-CLIP to demonstrate that RBM4 indeed bound ERV transcripts at CGG consensus elements. Loss of RBM4 resulted in elevated transcript level of bound ERVs of the HERV-K and -H families, as well as increased expression of HERV-K envelope protein. We pinpointed RBM4 regulation of HERV-K to a CGG-containing element that is conserved in the long terminal repeats (LTRs) of HERV-K-10 and -K-11, and validated the functionality of this site using reporter assays. In summary, we identified RBPs as potential regulators of ERV function and demonstrate a new role for RBM4 in controlling ERV expression.Significance StatementThe expression of endogenous retroviruses (ERVs) appears to have broad impact on human biology. Nevertheless, only a handful of transcriptional regulators of ERV expression are known and to our knowledge no RNA-binding proteins (RBPs) were yet implicated in positive or negative post-transcriptional regulation of ERVs. We implemented a computational pipeline that allowed us to identify RBPs that modulate ERV expression levels. Experimental validation of one of the prime candidates we identified, RBM4, showed that it indeed bound RNAs made from ERVs and negatively regulated the levels of those RNAs. We hereby identify a new layer of ERV regulation by RBPs.

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Section: Resultssupporting

confidence: 64%

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Foroushani

Chim

Wong

et al. 2020

Preprint

Self Cite

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“…Recently, insulin-like growth factor 2 mRNAbinding proteins (IGF2BPs) including IGF2BP1-3, are identified to bind m6A and function as readers. IGF2BPs promote RNA expression by enhancing RNA stability [78][79][80]. Eukaryotic initiation factor 3 (EIF3) facilitates cap-independent translation [23].…”

Section: Readersmentioning

confidence: 99%

“…IGF2BP3 participates in the fetal-adult hematopoietic switch through interacting with RNA-binding protein Lin28b. In B-cell progenitors, Lin28b and IGF2BP3 promote stability of mRNAs such as B-cell regulators Pax5 and Arid3a [79].…”

Section: Igf2bpsmentioning

confidence: 99%

Functions of N6-methyladenosine and its role in cancer

et al. 2019

Mol Cancer

916

816

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N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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“…Mitochondrial insults by exogenous agents can lead to dissipation of the mitochondrial membrane potential. [14] The integrity of the mitochondrial membrane potential in CSCs upon treatment with 1 was evaluated using the JC-1 assay. [15] HMLER-shEcad cells incubated with 1 (15 mm for 24 h) displayed asignificant increase in the population of cells with mitochondrial membrane depolarization (50 %increase compared to the untreated control;F igure 2B).…”

Section: Angewandte Chemiementioning

confidence: 99%

A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

et al. 2017

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The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.

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Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3

Cited by 58 publications

References 82 publications

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Functions of N6-methyladenosine and its role in cancer

A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

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