A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells

Li, Yapu; Wang, Ding; Wang, Hongtao; Huang, Xin; Wen, Yao; Wang, Bingrui; Xu, Changlu; Gao, Jie; Liu, Jinhua; Tong, Jiejuan; Wang, Mengge; Su, Pei; Ren, Sirui; Ma, Feng; Li, Hongdong; Bresnick, Emery H.; Zhou, Jiaxi; Shi, Lihong

doi:10.15252/embr.202050535

Cited by 10 publications

(12 citation statements)

References 87 publications

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“…Although the different NUMB isoforms may be responsible for diverse cellular phenotypes [27], our previous studies demonstrated that isoforms Numb1 and Numb4 possessed comparable suppressor activity in OSCC cells expressing endogenous NUMB [23]. The present study further established that both Numb1 and Numb4 were equally suppressive in OSCC subclones whose NUMB genome had been deleted.…”

Section: Discussionsupporting

confidence: 73%

“…CD44, CD147, or β-integrin interact with MCTs to act as chaperones or functional patterners [40][41][42]. Although the entire NUMB protein was required for the binding of NUMB with mGluR5 [28], during transdifferentiation from mesodermal cells to endothelial progenitor cells, the splicing factor mediated the induction of NUMB_S isoforms to regulate Notch signaling [27]. The present study demonstrated, for the first time, the presence of Numb4 and MCT1/MCT4 complexes, which may trigger proteasome degradation, although the PTB and PRR domains were absent in Numb4 [12].…”

Section: Discussionmentioning

confidence: 99%

“…The suppressor roles of NUMB against OSCC have been identified in previous studies [14,23], but its downstream effectors remain to be elucidated. The distinct functions mediated by six NUMB isoforms resulting from alternative splicing have been actively investigated [12,27]. We discovered that the NUMB isoforms Numb1 to Numb4 were capable of suppressing OSCC pathogenesis [23].…”

Section: Introductionmentioning

confidence: 99%

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miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

Chou

Chiang

Yang

et al. 2021

IJMS

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Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. miR-31 is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the miR-31-NUMB regulatory axis has been demonstrated in malignancies. Mitochondrial dysfunction and adaptation to glycolytic respiration are frequent events in malignancies. Monocarboxylate transporters (MCTs) function to facilitate lactate flux in highly glycolytic cells. Upregulation of MCT1 and MCT4 has been shown to be a prognostic factor of OSCC. Here, we reported that miR-31-NUMB can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes, MCT1 and MCT4 expression, lactate production, and glycolytic respiration in NUMB-deleted OSCC subclones. Transfection of the Numb1 or Numb4 isoform reversed the oncogenic induction elicited by NUMB deletion. This study also showed, for the first time, that NUMB4 binds MCT1 and MCT4 and that this binding increases their ubiquitination, which may decrease their abundance in cell lysates. The disruptions in oncogenicity and metabolism associated with miR-31 deletion and NUMB deletion were partially rescued by MCT1/MCT4 expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the miR-31-NUMB-MCT1/MCT4 regulatory cascade is present in oral carcinoma.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

Chou

Chiang

Yang

et al. 2021

IJMS

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“…mNUMB encodes six alternatively spliced transcripts ( 25 , 26 ). There are areas of functional overlap of these six isoforms, but physiological and pathological differences are distinct ( 24 , 25 , 27 - 29 ).…”

Section: The Numb Proteinmentioning

confidence: 99%

The role of NUMB/NUMB isoforms in cancer stem cells

Choi

Seok

Kang

et al. 2021

BMB Rep

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Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.

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“…Among them were SMG7, DDX, SRSF and HNRNP gene family members. Indeed, many recent reviews show that alternative splicing plays a vital role in the self-renewal, pluripotency and lineage specific differentiation of hematopoietic stem cells (Wong et al 2018; Goldstein et al 2017; Chen et al 2014; Li et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

Schmidt

Mays²,

Barefoot

et al. 2021

Preprint

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Bone marrow progenitor cell differentiation has frequently been used as a model for studying cellular plasticity and cell-fate decisions. Recent analysis at the level of single-cells has expanded knowledge of the transcriptional landscape of human hematopoietic cell lineages. Using single-molecule real-time (SMRT) full-length RNA sequencing, we have previously shown that human bone marrow lineage-negative (Lin-neg) cell populations contain a surprisingly diverse set of mRNA isoforms. Here, we report from single cell, full-length RNA sequencing that this diversity is also reflected at the single-cell level. From fresh human bone marrow unselected and lineage-negative progenitor cells were isolated by droplet-based single-cell selection (10xGenomics). The single cell-derived mRNAs were analyzed by full-length SMRT and short-read sequencing. In both samples we detected an average of 8000 different genes using short-read sequencing. Differential expression analysis arranged the single-cells of the total bone marrow into only four clusters whereas the Lin-neg population was much more diverse with nine clusters. mRNA isoform analysis of the single-cell populations using full-length sequencing revealed that Lin-neg cells contain on average 24% more novel splice variants than the total bone marrow cells. Interestingly, among the most frequent genes expressing novel isoforms were members of the spliceosome, e.g. HNRNPs, DEAD box helicases and SRSFs. Mapping the isoforms from all genes to the cell type clusters revealed that total bone marrow cells express novel isoforms only in a small subset of clusters. On the other hand, lineage-negative progenitor cells expressing novel isoforms were present in nearly all subpopulations. In conclusion, on a single-cell level lineage-negative cells express a higher diversity of genes and more alternatively spliced novel isoforms suggesting that cells in this subpopulation are poised for different fates.

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A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells

Cited by 10 publications

References 87 publications

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

The role of NUMB/NUMB isoforms in cancer stem cells

Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

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