A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells

Yamamoto, Katsuya; Goyama, Susumu; Asada, Shuhei; Fujino, Takeshi; Yonezawa, Taishi; Sato, Nobuko; Takeda, Reina; Tsuchiya, Akiho; Tanaka, Yosuke; Yokoyama, Akihiko; Toya, Hikaru; Kon, Ayana; Nannya, Yasuhito; Onoguchi‐Mizutani, Rena; Nakagawa, Shinichi; Hirose, Tetsuro; Ogawa, Seishi; Akimitsu, Nobuyoshi; Kitamura, Toshio

doi:10.1016/j.celrep.2021.109576

Cited by 21 publications

(18 citation statements)

References 76 publications

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“… 64 Mutations in ASXL1 histone modifier have also been linked to regulation of paraspeckle formation in hematopoietic cells. 65 Current research has mainly focused on TF binding and transcription initiation and a future challenge will be to examine how the condensates are associated with transcription cycles and how they are altered in cancers. Although the functional role of nuclear condensates in cancer cells remains to be elucidated, cancer may be associated with the alteration in various other nuclear condensates.…”

Section: Alteration In Transcriptional Condensates In Cancermentioning

confidence: 99%

Biomolecular condensates in cancer biology

Suzuki

Onimaru

2021

Cancer Science

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Understanding the characteristics of cancer cells is essential for the development of improved diagnosis and therapeutics. From a gene regulation perspective, the super‐enhancer concept has been introduced to systematically understand the molecular mechanisms underlying the identities of various cell types and has been extended to the analysis of cancer cells and cancer genome alterations. In addition, several characteristic features of super‐enhancers have led to the recognition of the link between gene regulation and biomolecular condensates, which is often mediated by liquid‐liquid phase separation. Several lines of evidence have suggested molecular and biophysical principles and their alterations in cancer cells, which are particularly associated with gene regulation and cell signaling (“ transcriptional” and “signaling” condensates). These findings collectively suggest that the modification of biomolecular condensates represents an important mechanism by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression. The condensate model also provides the molecular basis of the vulnerability of cancer cells to transcriptional perturbation and further suggests the possibility of therapeutic targeting of condensates. This review summarizes recent findings regarding the relationships between super‐enhancers and biomolecular condensate models, multiple scenarios of condensate alterations in cancers, and the potential of the condensate model for therapeutic development.

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Section: Alteration In Transcriptional Condensates In Cancermentioning

confidence: 99%

Biomolecular condensates in cancer biology

Suzuki

Onimaru

2021

Cancer Science

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“…Additional sex combs‐like 1 (ASXL1) is a member of the mammalian ASXL family. ASXL1 regulates gene expression and signal transduction through interactions with multiple proteins, such as BAP1, 7 EZH2, 8 BMI1, 9 BRD4, 10 AKT, 11,12 and NONO 13 . In addition to CHIP, ASXL1 is frequently mutated in myeloid malignancies and associated with poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…ASXL1 mutations are detected in the last exon, resulting in the translation of C‐terminally truncated ASXL1 proteins. The pathogenic ASXL1 mutants alter epigenetic modifications, 8,14–16 activate the AKT/mTOR pathway, 11 and disrupt paraspeckle formation 13 . We previously established conditional knock‐in mice carrying a C‐terminally truncated Asxl1 mutant with the floxed STOP cassette under the control of Rosa26 promoter 17 .…”

Section: Introductionmentioning

confidence: 99%

“…ASXL1 regulates gene expression and signal transduction through interactions with multiple proteins, such as BAP1, 7 EZH2, 8 BMI1, 9 BRD4, 10 AKT, 11 , 12 and NONO. 13 In addition to CHIP, ASXL1 is frequently mutated in myeloid malignancies and associated with poor prognosis. ASXL1 mutations are detected in the last exon, resulting in the translation of C‐terminally truncated ASXL1 proteins.…”

Section: Introductionmentioning

confidence: 99%

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CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression

et al. 2022

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Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated phenomenon characterized by clonal expansion of blood cells harboring somatic mutations in hematopoietic genes, including DNMT3A, TET2, and ASXL1. Clinical evidence suggests that CHIP is highly prevalent and associated with poor prognosis in solidtumor patients. However, whether blood cells with CHIP mutations play a causal role in promoting the development of solid tumors remained unclear. Using conditional knock-in mice that express CHIP-associated mutant Asxl1 (Asxl1-MT), we showed that expression of Asxl1-MT in T cells, but not in myeloid cells, promoted solid-tumor progression in syngeneic transplantation models. We also demonstrated that Asxl1-MT-expressing blood cells accelerated the development of spontaneous mammary tumors induced by MMTV-PyMT. Intratumor analysis of the mammary tumors revealed the reduced T-cell infiltration at tumor sites and programmed death receptor-1 (PD-1) upregulation in CD8 + T cells in MMTV-PyMT/Asxl1-MT mice. In addition, we found that Asxl1-MT induced T-cell dysregulation, including aberrant intrathymic T-cell development, decreased CD4/CD8 ratio, and naïve-memory imbalance in peripheral T cells. These results indicate that Asxl1-MT perturbs T-cell development and function, which contributes to creating a protumor microenvironment for solid tumors. Thus, our findings raise the possibility that ASXL1-mutated blood cells exacerbate solid-tumor progression in ASXL1-CHIP carriers.

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“…Subsequently, it has been shown that NONO is involved not only in splicing but also in gene expression regulation, mRNA processing, gene damage response, cell proliferation, apoptosis, migration, and various other cellular functions [15,41]. Recently, it has been shown that nuclear paraspeckle formation by the histone modifier ASXL1 and the function of NONO in the nuclear paraspeckle are essential for normal differentiation from hematopoietic stem and progenitor cells (HSPCs) [42]. NONO often forms heterodimers with SFPQ (splicing factor proline/glutamine rich), another human DBHS family protein, and exerts its function [15,41].…”

Section: The Biological Importance Of the Interaction Between Rex And...mentioning

confidence: 99%

Exploring New Functional Aspects of HTLV-1 RNA-Binding Protein Rex: How Does Rex Control Viral Replication?

Nakano

Yokoyama

Shin

et al. 2022

Viruses

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After integration to the human genome as a provirus, human T-cell leukemia virus type 1 (HTLV-1) utilizes host T cell gene expression machinery for viral replication. The viral RNA-binding protein, Rex, is known to transport unspliced/incompletely spliced viral mRNAs encoding viral structural proteins out of the nucleus to enhance virus particle formation. However, the detailed mechanism of how Rex avoids extra splicing of unspliced/incompletely spliced viral mRNAs and stabilizes them for effective translation is still unclear. To elucidate the underlying molecular mechanism of Rex function, we comprehensively analyzed the changes in gene expression and splicing patterns in Rex-overexpressing T cells. In addition, we identified 81 human proteins interacting with Rex, involved in transcription, splicing, translation, and mRNA quality control. In particular, Rex interacts with NONO and SFPQ, which play important roles in the regulation of transcription and splicing. Accordingly, expression profiles and splicing patterns of a wide variety of genes are significantly changed in Rex-expressing T cells. Especially, the level of vPD-L1 mRNA that lacks the part of exon 4, thus encodes soluble PD-L1 was significantly increased in Rex-expressing cells. Overall, by integrated analysis of these three datasets, we showed for the first time that Rex intervenes the host gene expression machinery throughout the pathway, probably to escort viral unstable mRNAs from transcription (start) to translation (end). Upon exerting its function, Rex may alter the expression level and splicing patterns of various genes, thus influencing the phenotype of the host cell.

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A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells

Cited by 21 publications

References 76 publications

Biomolecular condensates in cancer biology

Biomolecular condensates in cancer biology

CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression

Exploring New Functional Aspects of HTLV-1 RNA-Binding Protein Rex: How Does Rex Control Viral Replication?

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