Faculty Profiles - SUZUKI Hiroshi

Papers - SUZUKI Hiroshi

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Phase-separated super-enhancers confer an innate radioresistance on genomic DNA. Reviewed

Matsumoto K, Ikliptikawati DK, Makiyama K, Mochizuki K, Tobita M, Kobayashi I, Voon DC, Lim K, Ogawa K, Kashiwakura I, Suzuki HI, Yoshino H, Wong RW, Hazawa M

Journal of radiation research Vol. 65 ( 4 ) page： 482 - 490 2024.7

Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma. Reviewed

Enokido T, Horie M, Yoshino S, Suzuki HI, Matsuki R, Brunnström H, Micke P, Nagase T, Saito A, Miyashita N

Molecular cancer research : MCR 2023.10

TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation. Reviewed International journal

Miho M Suzuki, Kenta Iijima, Koichi Ogami, Keiko Shinjo, Yoshiteru Murofushi, Jingqi Xie, Xuebing Wang, Yotaro Kitano, Akira Mamiya, Yuji Kibe, Tatsunori Nishimura, Fumiharu Ohka, Ryuta Saito, Shinya Sato, Junya Kobayashi, Ryoji Yao, Kanjiro Miyata, Kazunori Kataoka, Hiroshi I Suzuki, Yutaka Kondo

Nature communications Vol. 14 ( 1 ) page： 4521 - 4521 2023.8

Language：English Publishing type：Research paper (scientific journal)

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

DOI： 10.1038/s41467-023-40243-8

Roles of MicroRNAs in Disease Biology. Reviewed

Hiroshi I Suzuki

JMA journal Vol. 6 ( 2 ) page： 104 - 113 2023.4

Language：English Publishing type：Research paper (scientific journal)

Gene regulation by microRNAs (miRNAs) plays important roles in development, physiology, and disease. miRNAs are an abundant class of noncoding RNAs that are generated through multistep biosynthetic pathways and typically repress gene expression through target destabilization and translational inhibition. Complex interactions between miRNAs and target mRNAs are associated with characteristic molecular mechanisms, including miRNA cotargeting, target-directed miRNA degradation, and crosstalk with various RNA-binding proteins. Consistent with the broad influence on cellular function, miRNA deregulation is commonly observed in various diseases, particularly cancer, with both tumor-suppressive and oncogenic roles. Mutations in the miRNA biosynthetic pathway and several miRNA genes have been linked to diverse types of cancer and a subset of genetic diseases, respectively. Additionally, super-enhancers play important roles in the regulation of cell type-specific and disease-associated miRNAs. This review summarizes the molecular features of miRNA biogenesis and target regulation along with the roles of miRNAs in disease biology, with recent examples expanding the pathophysiological roles of miRNAs.

DOI： 10.31662/jmaj.2023-0009

Optimization of Cas9 activity through the addition of cytosine extensions to single-guide RNAs. Reviewed International journal

Masaki Kawamata, Hiroshi I Suzuki, Ryota Kimura, Atsushi Suzuki

Nature biomedical engineering Vol. 7 ( 5 ) page： 672 - + 2023.4

Language：English Publishing type：Research paper (scientific journal)

The precise regulation of the activity of Cas9 is crucial for safe and efficient editing. Here we show that the genome-editing activity of Cas9 can be constrained by the addition of cytosine stretches to the 5'-end of conventional single-guide RNAs (sgRNAs). Such a 'safeguard sgRNA' strategy, which is compatible with Cas12a and with systems for gene activation and interference via CRISPR (clustered regularly interspaced short palindromic repeats), leads to the length-dependent inhibition of the formation of functional Cas9 complexes. Short cytosine extensions reduced p53 activation and cytotoxicity in human pluripotent stem cells, and enhanced homology-directed repair while maintaining bi-allelic editing. Longer extensions further decreased on-target activity yet improved the specificity and precision of mono-allelic editing. By monitoring indels through a fluorescence-based allele-specific system and computational simulations, we identified optimal windows of Cas9 activity for a number of genome-editing applications, including bi-allelic and mono-allelic editing, and the generation and correction of disease-associated single-nucleotide substitutions via homology-directed repair. The safeguard-sgRNA strategy may improve the safety and applicability of genome editing.

DOI： 10.1038/s41551-023-01011-7

Network Regulation of microRNA Biogenesis and Target Interaction Reviewed

Komatsu Shintaro, Kitai Hiroki, Suzuki Hiroshi I.

CELLS Vol. 12 ( 2 ) 2023.1

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis. Reviewed International journal

Hiroki Kitai, Noritoshi Kato, Koichi Ogami, Shintaro Komatsu, Yu Watanabe, Seiko Yoshino, Eri Koshi, Shoma Tsubota, Yoshio Funahashi, Takahiro Maeda, Kazuhiro Furuhashi, Takuji Ishimoto, Tomoki Kosugi, Shoichi Maruyama, Kenji Kadomatsu, Hiroshi I Suzuki

BMC biology Vol. 20 ( 1 ) page： 248 - 248 2022.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression ("neighborhood" miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. RESULTS: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites ("seed overlap" miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, "seed overlap" miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive "seed overlap" is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes-those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both "seed overlap" and "neighborhood" miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. CONCLUSIONS: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

DOI： 10.1186/s12915-022-01447-4

ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Reviewed International journal

Minglu Yan, Noriko Komatsu, Ryunosuke Muro, Nam Cong-Nhat Huynh, Yoshihiko Tomofuji, Yukinori Okada, Hiroshi I Suzuki, Hiroyuki Takaba, Riko Kitazawa, Sohei Kitazawa, Warunee Pluemsakunthai, Yuichi Mitsui, Takashi Satoh, Tadashi Okamura, Takeshi Nitta, Sin-Hyeog Im, Chan Johng Kim, George Kollias, Sakae Tanaka, Kazuo Okamoto, Masayuki Tsukasaki, Hiroshi Takayanagi

Nature immunology Vol. 23 ( 9 ) page： 1330 - 1341 2022.9

Language：English Publishing type：Research paper (scientific journal)

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.

DOI： 10.1038/s41590-022-01285-0

Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. Reviewed International journal

Yuko Shimamura, Kazuhiro Furuhashi, Akihito Tanaka, Munetoshi Karasawa, Tomoya Nozaki, Shintaro Komatsu, Kenshi Watanabe, Asuka Shimizu, Shun Minatoguchi, Makoto Matsuyama, Yuriko Sawa, Naotake Tsuboi, Takuji Ishimoto, Hiroshi I Suzuki, Shoichi Maruyama

Communications biology Vol. 5 ( 1 ) page： 753 - 753 2022.7

Language：English Publishing type：Research paper (scientific journal)

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

DOI： 10.1038/s42003-022-03712-2

ASCL1 regulates super-enhancer-associated miRNAs to define molecular subtypes of small cell lung cancer. Reviewed International journal

Kazuko Miyakawa, Naoya Miyashita, Masafumi Horie, Yasuhiro Terasaki, Hidenori Tanaka, Hirokazu Urushiyama, Kensuke Fukuda, Yugo Okabe, Takashi Ishii, Naomi Kuwahara, Hiroshi I Suzuki, Takahide Nagase, Akira Saito

Cancer science 2022.7

Language：English Publishing type：Research paper (scientific journal)

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1 and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3 and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA-sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs such as miR-7, miR-375, miR-200b-3p and miR-429, leading to repression of their targets whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC; for example, co-targeting of YAP1 by miR-9 and miR-375. Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.

DOI： 10.1111/cas.15481

The molecular understanding of super-enhancer dysregulation in cancer. Reviewed

Seiko Yoshino, Hiroshi I Suzuki

Nagoya journal of medical science Vol. 84 ( 2 ) page： 216 - 229 2022.5

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Abnormalities in the regulation of gene expression are associated with various pathological conditions. Among the distal regulatory elements in the genome, the activation of target genes by enhancers plays a central role in the formation of cell type-specific gene expression patterns. Super-enhancers are a subclass of enhancers that frequently contain multiple enhancer-like elements and are characterized by dense binding of master transcription factors and Mediator complexes and high signals of active histone marks. Super-enhancers have been studied in detail as important regulatory regions that control cell identity and contribute to the pathogenesis of diverse diseases. In cancer, super-enhancers have multifaceted roles by activating various oncogenes and other cancer-related genes and shaping characteristic gene expression patterns in cancer cells. Alterations in super-enhancer activities in cancer involve multiple mechanisms, including the dysregulation of transcription factors and the super-enhancer-associated genomic abnormalities. The study of super-enhancers could contribute to the identification of effective biomarkers and the development of cancer therapeutics targeting transcriptional addiction. In this review, we summarize the roles of super-enhancers in cancer biology, with a particular focus on hematopoietic malignancies, in which multiple super-enhancer alteration mechanisms have been reported.

DOI： 10.18999/nagjms.84.2.216

Biomolecular condensates in cancer biology. Reviewed International journal

Hiroshi I Suzuki, Koh Onimaru

Cancer science Vol. 113 ( 2 ) page： 382 - 391 2022.2

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/cas.15232

Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function. Reviewed International journal

Koichi Ogami, Hiroshi I Suzuki

International journal of molecular sciences Vol. 22 ( 24 ) 2021.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The genome is pervasively transcribed across various species, yielding numerous non-coding RNAs. As a counterbalance for pervasive transcription, various organisms have a nuclear RNA exosome complex, whose structure is well conserved between yeast and mammalian cells. The RNA exosome not only regulates the processing of stable RNA species, such as rRNAs, tRNAs, small nucleolar RNAs, and small nuclear RNAs, but also plays a central role in RNA surveillance by degrading many unstable RNAs and misprocessed pre-mRNAs. In addition, associated cofactors of RNA exosome direct the exosome to distinct classes of RNA substrates, suggesting divergent and/or multi-layer control of RNA quality in the cell. While the RNA exosome is essential for cell viability and influences various cellular processes, mutations and alterations in the RNA exosome components are linked to the collection of rare diseases and various diseases including cancer, respectively. The present review summarizes the relationships between pervasive transcription and RNA exosome, including evolutionary crosstalk, mechanisms of RNA exosome-mediated RNA surveillance, and physiopathological effects of perturbation of RNA exosome.

DOI： 10.3390/ijms222413401

MCPIP1 reduces HBV-RNA by targeting its epsilon structure. Reviewed International journal

Yingfang Li, Lusheng Que, Kento Fukano, Miki Koura, Kouichi Kitamura, Xin Zheng, Takanobu Kato, Hussein Hassan Aly, Koichi Watashi, Senko Tsukuda, Hideki Aizaki, Noriyuki Watanabe, Yuko Sato, Tadaki Suzuki, Hiroshi I Suzuki, Kazuyoshi Hosomichi, Makoto Kurachi, Kousho Wakae, Masamichi Muramatsu

Scientific reports Vol. 10 ( 1 ) page： 20763 - 20763 2020.11

Language：English Publishing type：Research paper (scientific journal)

Hepatitis B virus (HBV) is the major causative factor of chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. We previously demonstrated that a proinflammatory cytokine IL-1β reduced the level of HBV RNA. However, the mechanism underlying IL-1β-mediated viral RNA reduction remains incompletely understood. In this study, we report that immune regulator Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) can reduce HBV RNA in hepatocytes. MCPIP1 expression level was higher in the liver tissue of HBV-infected patients and mice. Overexpression of MCPIP1 decreased HBV RNA, whereas ablating MCPIP1 in vitro enhanced HBV production. The domains responsible for RNase activity or oligomerization, were required for MCPIP1-mediated viral RNA reduction. The epsilon structure of HBV RNA was important for its antiviral activity and cleaved by MCPIP1 in the cell-free system. Lastly, knocking out MCPIP1 attenuated the anti-HBV effect of IL-1β, suggesting that MCPIP1 is required for IL-1β-mediated HBV RNA reduction. Overall, these results suggest that MCPIP1 may be involved in the antiviral effect downstream of IL-1β.

DOI： 10.1038/s41598-020-77166-z

FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms. Reviewed International journal

Naoya Miyashita, Masafumi Horie, Hiroshi I Suzuki, Minako Saito, Yu Mikami, Kenichi Okuda, Richard C Boucher, Maho Suzukawa, Akira Hebisawa, Akira Saito, Takahide Nagase

American journal of respiratory cell and molecular biology Vol. 63 ( 6 ) page： 831 - 842 2020.9

Language：English Publishing type：Research paper (scientific journal)

Fibroblasts provide a structural framework for multiple organs, and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of forkhead box L1 (FOXL1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcript levels associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, in contrast to fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ/YAP signature genes and PDGF receptor-α. FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis (IPF) lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor, and is involved in IPF pathogenesis.

DOI： 10.1165/rcmb.2019-0396OC

Chd4 choreographs self-antigen expression for central immune tolerance. Reviewed International journal

Yoshihiko Tomofuji, Hiroyuki Takaba, Hiroshi I Suzuki, Rayene Benlaribi, Cristian David Peña Martinez, Yoshihiro Abe, Yasuyuki Morishita, Tadashi Okamura, Akashi Taguchi, Tatsuhiko Kodama, Hiroshi Takayanagi

Nature immunology Vol. 21 ( 8 ) page： 892 - 901 2020.6

Language：English Publishing type：Research paper (scientific journal)

Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.

DOI： 10.1038/s41590-020-0717-2

Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes. Reviewed International journal

Yotaro Ochi, Ayana Kon, Toyonori Sakata, Masahiro M Nakagawa, Naotaka Nakazawa, Masanori Kakuta, Keisuke Kataoka, Haruhiko Koseki, Manabu Nakayama, Daisuke Morishita, Tatsuaki Tsuruyama, Ryunosuke Saiki, Akinori Yoda, Rurika Okuda, Tetsuichi Yoshizato, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Shinichi Kotani, Yasunori Kogure, Nobuyuki Kakiuchi, Tomomi Nishimura, Hideki Makishima, Luca Malcovati, Akihiko Yokoyama, Kengo Takeuchi, Eiji Sugihara, Taka-Aki Sato, Masashi Sanada, Akifumi Takaori-Kondo, Mario Cazzola, Mineko Kengaku, Satoru Miyano, Katsuhiko Shirahige, Hiroshi I Suzuki, Seishi Ogawa

Cancer discovery Vol. 10 ( 6 ) page： 836 - 853 2020.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.This article is highlighted in the In This Issue feature, p. 747.

DOI： 10.1158/2159-8290.CD-19-0982

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis. Reviewed International journal

Matsuyama H, Suzuki HI

International Journal of Molecular Sciences Vol. 21 ( 1 ) 2019.12

TGF-β Signaling in Cellular Senescence and Aging-Related Pathology. Reviewed International journal

Kana Tominaga, Hiroshi I Suzuki

International Journal of Molecular Sciences Vol. 20 ( 20 ) 2019.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer's disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases.

DOI： 10.3390/ijms20205002

Sequestration of microRNA-mediated target repression by the Ago2-associated RNA-binding protein FAM120A. Reviewed International journal

Kelly TJ, Suzuki HI, Zamudio JR, Suzuki M, Sharp PA

RNA (New York, N.Y.) Vol. 25 ( 10 ) page： 1291 - 1297 2019.10

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