Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110δ

Zhou, Tong; Luo, Man; Cai, Wei; Zhou, Siyuan; Feng, D; Xu, Chao; Wang, Hongyan

doi:10.1016/j.ebiom.2018.04.023

Cited by 135 publications

(110 citation statements)

References 52 publications

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“…Runx1 might function to keep cardiomyocyte proliferation in check and to prevent it from getting out of control during myocardial regeneration. This fits well with the observations that Runx1 acts as a key factor in determining the proliferative and differential state of multiple cell-types (23,(45)(46)(47)(48) alongside different functions that correlate with level of Runx1 expression (49,50), with higher levels shown to result in cell fate transition and differentiation (51).…”

Section: Discussionsupporting

confidence: 89%

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. Here, we report how runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, but unexpectedly, absence of runx1 results in enhanced regeneration. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes without differentiating into myofibroblasts. Both these populations are absent in runx1 mutants, resulting in a less collagenous and fibrinous scar. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and by upregulation of components of the fibrin degradation pathway, including plasminogen receptor Annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of Plasminogen. In addition, we find enhanced myocardial proliferation as well as increased myocardial survival in the mutant. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell-types and that targeting Runx1 is a novel therapeutic strategy to induce endogenous heart repair.

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Section: Discussionsupporting

confidence: 89%

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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“…There was decreased expression of the Na+/Ca++ exchanger (NCX), SLC8A1 (LFC=-0.57, p=7.0e-28), which has been reported in experimental models of diabetes (44) and evidence for alteration of SLIT-ROBO signaling with an increase in ROBO2 (LFC=0.98, p=8.4e=10) and a decrease in SLIT2 (LFC=-0.27, p=3.7e-08). We observed increased expression of the transcription factor, RUNX1, in both the late distal convoluted tubule (LFC=0.66, p=3.3e-17) and principal cells (LFC=0.71, p=1e-17), which may promote renal fibrosis (45).…”

Section: Diabetes Induces Gene Expression Changes That Promote Potassmentioning

confidence: 77%

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

Wilson

Kirita

et al. 2019

Preprint

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Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-typespecific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K + -ATPase, WNK1, mineralocorticoid receptor and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy. Significance StatementSingle nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.

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“…to changes in tissue architecture that promote tumour development. SERPINH1 also associates with enhanced TGFβ signalling and both RUNX1 and RUNX2 have been shown to be involved in TGFβ induced kidney fibrosis (23,59). The role of collagen in ccRCC is currently unclear, however collagen density and alignment have recently been shown to be significantly higher in patients with high grade tumours compared to low grade (60).…”

Section: Discussionmentioning

confidence: 99%

“…To date, very little is known about a functional role for RUNX1 in either normal kidney development or kidney cancer. There is some evidence of increased expression of a RUNX1 chromosomal translocation product in ccRCC patient samples (22) and RUNX1 has been shown to be expressed in mouse models of kidney fibrosis (a feature of chronic kidney disease correlated with RCC), involving RUNX regulation of TGFβ driven EMT (23).…”

Section: Introductionmentioning

confidence: 99%

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome

et al. 2020

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The recurring association of specific genetic lesions with particular types of cancer is a fascinating, and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown pro-tumorigenic role for the RUNX genes in this disease setting. Analysis of patient tumor biopsies together with loss of function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared to patients with low expression. This was functionally relevant as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability in vitro and in vivo. Transcriptional profiling of RUNX1-CRISPR-deleted cells revealed a gene signature dominated by extracellular matrix remodelling, notably affecting STMN3, SERPINH1, and EPHRIN signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC. Significance: These data reveal a novel unexplored oncogenic role for RUNX genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC. Research.

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Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110δ

Cited by 135 publications

References 52 publications

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome

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