Biology subjects

Aji, R.

Publications and source records attributed to Aji, R..

7 recordsLinked to original sources

bioRxiv2026

NSD2 deficiency disrupts the epigenetic landscape of cochlear hair cells to enhance ECM expression and to perturb cochlear hair cell function

Mammalian cochlear hair cells (HC) are crucial for hearing, and histone modifications may play an important role in HC maturation and functions. However, whether and how NSD2, a histone H3 lysine 36 (H3K36) dimethyltransferase, affects cochlear HC maturation remains unclear. Here, we established an HC-specific Nsd2 knockout mouse model and discovered that the loss of NSD2 results in severe structural defects in stereociliary bundles and profound hearing impairment. Integrated multi-omics profiling revealed that NSD2 deficiency leads to a decreased expression of H3K36me2, which in turn alters genome-wide chromatin accessibility and gene expression. Mechanistically, NSD2 deficiency triggers the aberrant upregulation of extracellular matrix (ECM) genes at the transcriptional level, causing excessive collagen accumulation and compromising tissue structure. Crucially, ECM intervention can mitigate NSD2-deficiency mediated hearing damage. Our study reveals an epigenetic mechanism by which NSD2 regulates cochlear HC maturation through inhibition of chromatin remodeling-induced ECM accumulation, and provides a potential new therapeutic direction for hearing impairment.

cell biology↗

bioRxiv2025

Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and prevent cell senescence.

The self-renewal capacity of intestinal stem cells (ISCs) declines with aging, leading to a loss of homeostasis and an increased susceptibility to intestinal diseases. Despite the established significance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms that connect these processes to aging-related ISC dysfunction remain elusive. Here, we demonstrate that Histone 3 lysine 36 trimethylation (H3K36me3) caused by SETD2 is critical for ISC stemness. We found that H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO) metabolism, and induces ISC senescence. Mechanistically, the loss of H3K36me3 triggers the activity of the SWI/SNF chromatin remodeling complex and leads to increased chromatin accessibility and enhancer activation, which alters FAO- and senescence-related gene expression. Importantly, we discover that metabolic intervention can prevent the senescence of ISC due to H3K36me3 deficiency. Our findings reveal a crucial role for H3K36me3 in maintaining the epigenetic landscape that orchestrates FAO metabolism and determines intestinal stem cell functions, emphasizing the role of FAO as a key modulator between H3K36me3 and ISC aging, suggesting that metabolic intervention may help mitigate age-related ISC dysfunction.

cell biology↗

bioRxiv2024

NSD2 promotes cell durotaxis and drives the transition from PKD to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase which has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances the cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.

cancer biology↗

bioRxiv2024

Epithelial NSD2 maintains FMOs-mediated taurine biosynthesis to prevent intestinal barrier disruption

Inflammatory bowel disease (IBD) poses a significant challenge due to its intricate pathogenesis. NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, is associated with transcriptional activation. However, the precise role of NSD2 in IBD remains unexplored. In this study, we discovered a downregulation of NSD2 in both the intestinal epithelial cells (IECs) of patients and the IBD mouse model. Deficiency of NSD2 in mouse IECs aggravated epithelial barrier disruption and inflammatory response in IBD. Mechanically, NSD2 loss downregulated H3K36me2 and FMO (taurine-synthesis enzyme) mRNA in IECs, resulting in decreased taurine biosynthesis in IECs. Importantly, supplementation with taurine significantly attenuated the symptoms of NSD2 deficiency-induced IBD. These data demonstrate that NSD2 plays a pivotal role in maintaining FMOs-mediated taurine biosynthesis to prevent intestinal inflammation. Our findings also underscore the importance of NSD2-H3K36me2-mediated taurine biosynthesis in maintaining intestinal mucosal barrier homeostasis.

cell biology↗

bioRxiv2022

SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. An important intrinsic cause of renal fibrosis is epigenetic alterations. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalyzing H3K36 dimethylation to trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Clinical data indicate that SETD2 is lowly expressed in patients with renal fibrosis. Here, we established genetically engineered mice with SETD2 and VHL deficiency. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the TGF-{beta}/Smad signaling pathway, thereby preventing the activation of the TGF-{beta}/Smad signaling pathway. Deletion of SETD2 leads to reduced smad7 expression, which results in activation of the TGF-{beta}/Smad signaling pathway and ultimately fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-{beta}/Smad signaling pathway in renal fibrogenesis. Thus, our study provides innovative insights into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

molecular biology↗

bioRxiv2020

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a relatively new antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cancer cells (LNCaP) but not in human lung cancer cells or patient-derived lung organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, enzalutamide showed no antiviral activity due to the AR independence of TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19.

microbiology↗

bioRxiv2020

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

While cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer pro-luminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we have identified that ERG highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibits its normal plasticity to transdifferentiate into basal lineage and ERG supersedes PTEN-loss which favors basal differentiation. ERG knock-out disrupted prostate cell luminal differentiation, whereas AR knock-out had no such effects. Trp63 is a known master regulator of prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG binds and inhibits the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG orchestrates chromatin interactions and regulates prostate cell lineage toward pro-luminal program, as its fundamental role on lineage differentiation in prostate cancer initiation.

cancer biology↗