Li Li

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.

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.

Background: Disruption of host–microbiota homeostasis is a fundamental hallmark of inflammatory bowel disease (IBD) pathogenesis. Host epigenetic modifications and corresponding alterations in gene expression levels can impact the composition of gut microbes. SET domain containing 2 (SETD2) is a critical epigenetic regulator with established tumor‐suppressive roles, but its function in intestinal microbial ecology and colitis progression remains unexplored. We aimed to investigate the specific role of SETD2 in maintaining gut microbial homeostasis and modulating colitis progression. Methods: RNA sequencing (RNA‐seq), assay for transposase‐accessible chromatin with high‐throughput sequencing (ATAC‐seq) and cleavage under targets and tagmentation sequencing (CUT&Tag‐seq) were conducted on colonic epithelial cells from intestinal epithelial cell‐specific SETD2 knockout (Setd2 ^vil‐ko ) mice to identify key mediators contributing to colitis development. Faecal samples underwent 16S rRNA sequencing and non‐targeted metabolomics analysis to characterise microbial dysbiosis and metabolic perturbations. Molecular experiments and faecal microbiome transplantation experiment were conducted to explore and validate the role of SETD2 in colitis development. Results: SETD2 deficiency induced overproduction of Reg3 lectins and disrupted gut microbiota composition. Beneficial commensal bacteria were depleted and dysregulated metabolites were accumulated in Setd2 ^vil‐ko mice. Supplementation with healthy‐like gut microbiota significantly ameliorated the exacerbated colitis induced by SETD2 deficiency. Conclusions: Our findings uncover a previously unrecognised role for SETD2 in maintaining microbial homeostasis, offering new mechanistic insights into how epigenetic regulation preserves intestinal homeostasis and suggesting novel therapeutic avenues for IBD.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What’s more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

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 hypothesize that histone 3 lysine 36 trimethylation (H3K36me3) might act as a bridge between these processes. In this study, we demonstrate that H3K36me3 caused by SETD2 is critical for ISC stemness. H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO), and promotes 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, our data demonstrate 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 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.

Strict regulation of epithelial cells is crucial for maintaining intestinal barrier integrity and preventing intestinal diseases. While transcriptional regulation is well recognized as vital in this process, translational regulation is equally important. SETD2, a methyltransferase, is involved in transcriptional regulation to maintain intestinal epithelial barrier function. However, its role in translation remains largely unexplored. Here, we found SETD2 deficiency leads to the downregulation of ribosome biogenesis progress coupled with transcriptome‐proteome discordance. Further ribosome profiling sequencing analyses showed reduced translational efficiency of cell adhesion and junction signatures in impaired intestinal epithelial barrier. Mechanistically, SETD2 ablation causes dysregulation and recruitment disorders of ribosome biogenesis factors, impairing the composition and distribution of ribosomal proteins. This disruption of ribosome biogenesis and homeostasis results in translational disorder of barrier maintenance genes, thereby compromising the intestinal barrier. Collectively, our findings unveil a previously unappreciated role of ribosome biogenesis and translational regulation in safeguarding intestinal epithelial barrier, and disclose a previously undiscovered role of SETD2 in modulating ribosome homeostasis.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase that 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 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.

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.

Rationale: Inflammatory bowel disease (IBD) is a relapsing and idiopathic disorder. The low therapeutic efficacy of IBD urgently prompts us to seek new treatment methods.

Background: Inflammatory bowel disease (IBD) presents 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. NSD2 expression is decreased in both the intestinal epithelial cells (IECs) of IBD patients and the IBD mouse model. However, the precise role of NSD2 in IBD remains unexplored.Methods: Colon tissues from IBD mice, SW620 cells and MC38 cells, were used as research subjects. Clinical databases of IBD patients were analysed to investigate whether NSD2 expression is reduced in the occurrence of IBD. NSD2‐knockout mice were generated to further investigate the role of NSD2 in IBD. The IECs were isolated for RNA sequencing and chromatin immunoprecipitation sequencing to identify molecular signalling pathways and key molecules leading to IBD in mice. Molecular and cellular experiments were conducted to analyse and validate the role of NSD2 in the development of IBD. Finally, rescue experiments were performed to confirm the molecular mechanism of NSD2 in the development of IBD.Results: Deficiency of NSD2 in mouse IECs aggravated epithelial barrier disruption and inflammatory response in IBD. Mechanistically, NSD2 loss led to downregulation of H3K36me2 and flavin‐containing monooxygenase (FMO) (taurine‐synthesis enzyme) mRNA, resulting in decreased taurine biosynthesis in IECs. Significantly, supplementation with taurine markedly alleviated the symptoms of NSD2 deficiency‐induced IBD.Conclusions: These data demonstrate that NSD2 plays a pivotal role in maintaining FMO‐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.Key points: In this study, we investigated the role of the histone methyltransferase NSD2 in preventing intestinal barrier disruption by sustaining taurine biosynthesis. NSD2 levels were reduced in both human specimens and mouse models of IBD. We demonstrate that NSD2 loss hinders the process of taurine synthesis in intestinal cells, leading to increased intestinal inflammation. Supplementation with taurine significantly relieved the symptoms caused by NSD2 deficiency. These data suggest that maintenance of NSD2‐mediated taurine biosynthesis is vital for preserving the intestinal barrier and attenuating inflammation.