The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction.

SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A's ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.

EZH2 as a major histone methyltransferase in PDGF-BB-activated orbital fibroblast in the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is an extra-thyroidal complication of Graves' disease which can lead to vision loss in severe cases. Currently, treatments of GO are not sufficiently effective, so novel therapeutic strategies are needed. As platelet-derived growth factor (PDGF)-BB induces several effector mechanisms in GO orbital fibroblasts including cytokine production and myofibroblast activation, this study aims to investigate the roles of histone lysine methyltransferases (HKMTs) in PDGF-BB-activated GO orbital fibroblasts by screening with HKMTs inhibitors library. From the total of twelve selective HKMT inhibitors in the library, EZH2, G9a and DOT1L inhibitors, DZNeP, BIX01294 and Pinometostat, respectively, prevented PDGF-BB-induced proliferation and hyaluronan production by GO orbital fibroblasts. However, only EZH2 inhibitor, DZNeP, significantly blocked pro-inflammatory cytokine production. For the HKMTs expression in GO orbital fibroblasts, PDGF-BB significantly and time-dependently induced EZH2, G9a and DOT1L mRNA expression. To confirm the role of EZH2 in PDGF-BB-induced orbital fibroblast activation, EZH2 silencing experiments revealed suppression of PDGF-BB-induced collagen type I and α-SMA expression along with decreasing histone H3 lysine 27 trimethylation (H3K27me3) level. In a more clinically relevant model than orbital fibroblast culture experiments, DZNeP treated GO orbital tissues significantly reduced pro-inflammatory cytokine production while slightly reduced ACTA2 mRNA expression. Our data is the first to demonstrate that among all HKMTs EZH2 dominantly involved in the expression of myofibroblast markers in PDGF-BB-activated orbital fibroblast from GO presumably via H3K27me3. Thus, EZH2 may represent a novel therapeutics target for GO.

Identification of Novel NSD1 variations in four Pediatric cases with sotos Syndrome.

OBJECTIVE: Sotos syndrome (SOTOS) is an uncommon genetic condition that manifests itself with the following distinctive features: prenatal overgrowth, facial abnormalities, and intellectual disability. This disorder is often associated with haploinsufficiency of the nuclear receptor-binding SET domain protein 1 (NSD1)gene. We investigated four pediatric cases characterized by early-onset overgrowth and developmental delay. The primary objective of this study was to achieve accurate genetic diagnoses. DESIGN&METHODS: A sequential analysis approach comprising chromosomal karyotyping, whole exome sequencing, and microarray analysis was conducted. RESULTS: All four cases exhibited variations in the NSD1 gene, with the identification of four previously unreported de novo variants, each specific to one case.Specifically, Case 1 carried the NSD1 (NM_022455): c.2686 C > T(p.Q896X) variant, Case 2 had the NSD1 (NM_022455): c.2858_2859delCT(p.S953X) variant, Case 3 displayed a chromosomal aberration, chr5: 5q35.2q35.3(176,516,604-176,639,249)×1, which encompassed the 5'-untranslated region of NSD1, and Case 4 harbored the NSD1 (NM_022455): c.6397T > G(p.C2133G) variant. CONCLUSION: This study not only provided precise diagnoses for these cases but also supplied significant evidence to facilitate informed consultations. Furthermore, our findings expanded the spectrum of mutations associated with SOTOS.

MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription.

MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.

MLL1 histone methyltransferase and UTX histone demethylase functionally cooperate to regulate the expression of NRF2 in response to ROS-induced oxidative stress.

The transcription factor NRF2 plays a pivotal role in maintaining redox and metabolic homeostasis by orchestrating oxidative stress-dependent transcription programs. Despite growing evidence implicating various cellular components in the regulation of NRF2 activity at the posttranslational stage, relatively less is known about the factors dictating the transcriptional activation of NRF2 in response to oxidative stress. In this study, we report the crucial roles of MLL1, an H3K4-specific methyltransferase, and UTX, an H3K27-specific histone demethylase, in the NRF2-dependent transcription program under oxidative stress. We find that the depletion of MLL1 or UTX results in increased susceptibility to oxidative stress, accompanied by higher intracellular ROS and the failed activation of antioxidant genes, including NRF2. In addition, MLL1 and UTX selectively target the NRF2 promoter, and exogenous FLAG-NRF2 expression increases the viability of MLL1-or UTX-depleted cells upon exposure to hydrogen peroxide. RNA-seq analysis demonstrates that depletion of MLL1 or UTX affects the changes in NRF2-dependent transcriptome in response to oxidative stress. Furthermore, ChIP and ChIP-seq analyses find that MLL1 and UTX functionally cooperate to establish a chromatin environment that favors active transcription at the H3K4me3/H3K27me3 bivalent NRF2 promoter in response to ROS-induced oxidative stress. Collectively, these findings provide a molecular mechanism underlying the cellular response to oxidative stress and highlight the importance of the chromatin structure and function in maintaining redox homeostasis.

Selfish conflict underlies RNA-mediated parent-of-origin effects.

Genomic imprinting-the non-equivalence of maternal and paternal genomes-is a critical process that has evolved independently in many plant and mammalian species1,2. According to kinship theory, imprinting is the inevitable consequence of conflictive selective forces acting on differentially expressed parental alleles3,4. Yet, how these epigenetic differences evolve in the first place is poorly understood3,5,6. Here we report the identification and molecular dissection of a parent-of-origin effect on gene expression that might help to clarify this fundamental question. Toxin-antidote elements (TAs) are selfish elements that spread in populations by poisoning non-carrier individuals7-9. In reciprocal crosses between two Caenorhabditis tropicalis wild isolates, we found that the slow-1/grow-1 TA is specifically inactive when paternally inherited. This parent-of-origin effect stems from transcriptional repression of the slow-1 toxin by the PIWI-interacting RNA (piRNA) host defence pathway. The repression requires PIWI Argonaute and SET-32 histone methyltransferase activities and is transgenerationally inherited via small RNAs. Remarkably, when slow-1/grow-1 is maternally inherited, slow-1 repression is halted by a translation-independent role of its maternal mRNA. That is, slow-1 transcripts loaded into eggs-but not SLOW-1 protein-are necessary and sufficient to counteract piRNA-mediated repression. Our findings show that parent-of-origin effects can evolve by co-option of the piRNA pathway and hinder the spread of selfish genes that require sex for their propagation.

Characterization of the Pristionchus pacificus "epigenetic toolkit" reveals the evolutionary loss of the histone methyltransferase complex PRC2.

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation-or lack thereof-of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the "epigenetic toolkit" available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with Caenorhabditis elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to compare with C. elegans. This inventory will enable reverse-genetic experiments related to plasticity and has revealed the first loss of PRC2 in a multicellular organism.

Controllers of histone methylation-modifying enzymes in gastrointestinal cancers.

Gastrointestinal (GI) cancers have been considered primarily genetic malignancies, caused by a series of progressive genetic alterations. Accumulating evidence shows that histone methylation, an epigenetic modification program, plays an essential role in the different pathological stages of GI cancer progression, such as precancerous lesions, tumorigenesis, and tumor metastasis. Histone methylation-modifying enzymes, including histone methyltransferases (HMTs) and demethylases (HDMs), are the main executor of post-transcriptional modification. The abnormal expression of histone methylation-modifying enzymes characterizes GI cancers with complex pathogenesis and progression. Interactions between upstream controllers and histone methylation-modifying enzymes have recently been revealed, and have provided numerous opportunities to elucidate the pathogenesis of GI cancers in depth and clearly. Here we focus on the association between histone methylation-modifying enzymes and their controllers, aiming to provide a new perspective on the molecular research and clinical management of GI cancers.

Histone methyltransferase SETD2 is required for proper hippocampal lamination and neuronal maturation.

Proper formation of the hippocampus is crucial for the brain to execute memory and learning functions. However, many questions remain regarding how pyramidal neurons (PNs) of the hippocampus mature and precisely position. Here we revealed that Setd2, the methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), is essential for the precise localization and maturation of PNs in the hippocampal CA1. The ablation of Setd2 in neural progenitors leads to irregular lamination of the CA1 and increased numbers of PNs in the stratum oriens. Setd2 deletion in postmitotic neurons causes mislocalization and immaturity of CA1 PNs. Transcriptome analyses revealed that SETD2 maintains the expressions of clustered protocadherin (cPcdh) genes. Together, Setd2 is required for proper hippocampal lamination and maturation of CA1 PNs.

The first pineoblastoma case report of a patient with Sotos syndrome harboring NSD1 germline mutation.

Germline mutations of NSD1 are associated with Sotos syndrome, characterized by distinctive facial features, overgrowth, and developmental delay. Approximately 3% of individuals with Sotos syndrome develop tumors. In this study, we describe an infant in pineoblastoma with facial anomalies, learning disability and mild autism at 1 years diagnosed as Sotos syndrome owing to carrying a novel mutation de novo germline NSD1 likely pathogenic variant. This patient expands both the mutation and phenotype spectrum of the Sotos Syndrome and provides new clinical insights into the potential mechanism of underlying pinealoblastoma pathology.

The histone methyltransferase SMYD1 is induced by thermogenic stimuli in adipose tissue.

Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Results: SMYD1 expression increased in WAT of high-fat diet fed mice and in WAT and brown adipose tissue of cold-exposed mice, suggesting its role in thermogenesis. SMYD1 expression was higher in beige adipocytes than in white adipocytes, and its silencing leads to a decrease in mitochondrial content and in Pgc-1α expression. Conclusion: These data suggest a novel role for SMYD1 as a positive regulator of energy control in adipose tissue.

In this study, a protein called SMYD1 was examined in the adipose tissue of mice to understand its role in the development of different types of fat cells. The authors used mice fed a high-fat diet or mice exposed to a cold environment. The experiments were also performed on cultured cells that were stimulated to form specific types of fat cells (white adipocytes, which store energy; or beige adipocytes, which are responsible for releasing energy in the form of heat). The study found that SMYD1 increased in white adipose tissue particularly in response to cold exposure and high-fat diet, suggesting involvement in body temperature regulation. SMYD1 was higher in beige adipocytes than in white fat cells, and when SMYD1 was reduced, there was a decrease in certain factors related to energy control. Overall, these results suggest that SMYD1 plays a novel role in energy regulation in adipose tissues.

Inhibition of the histone methyltransferase EZH2 induces vascular stiffness.

Vascular stiffness increases with aging, obesity and hypertension and predicts cardiovascular risk. The levels of histone H3-lysine-27 methylation (H3K27me) and the histone methyltransferase EZH2 both decrease in aging vessels, driving vascular stiffness. The impact of EZH2 inhibitors on vascular stiffness is unknown. We tested the hypothesis that the EZH2 inhibitor GSK126, currently in development for cancer treatment, increases vascular stiffness and explored underlying molecular mechanisms. Young (3 month) and middle-aged (12 month) male mice were treated with GSK126 for 1-2 months and primary human aortic smooth muscle cells (HASMCs) from young male and female donors were treated with GSK126 for 24-48 h. Stiffness was measured in vivo by pulse wave velocity and in vitro by atomic force microscopy (AFM) and vascular structure was quantified histologically. Extracellular matrix proteins were studied by qRT-PCR, immunoblotting, zymography and chromatin immunoprecipitation. GSK126 treatment decreased H3K27 methylation (H3K27me) and increased acetylation (H3K27ac) in mouse vessels and in HASMCs. In GSK126-treated mice, aortic stiffness increased without changes in vascular fibrosis. EZH2 inhibition enhanced elastin fiber degradation and matrix metalloprotease-2 (MMP2) expression. In HASMCs, GSK126 treatment increased synthetic phenotype markers and intrinsic HASMCs stiffness by AFM with altered cytoskeletal structure and increased nuclear actin staining. GSK126 also increased MMP2 protein expression, activity and enrichment of H3K27ac at the MMP2 promoter in HASMCs. GSK126 causes vascular stiffening, inducing MMP2 activity, elastin degradation, and modulation of SMC phenotype and cytoskeletal stiffness. These findings suggest that EZH2 inhibitors used to treat cancer could negatively impact the vasculature by enhancing stiffness and merits examination in human trials.

The molecular basis of cell memory in mammals: The epigenetic cycle.

Cell memory refers to the capacity of cells to maintain their gene expression program once the initiating environmental signal has ceased. This exceptional feature is key during the formation of mammalian organisms, and it is believed to be in part mediated by epigenetic factors that can endorse cells with the landmarks required to maintain transcriptional programs upon cell duplication. Here, we review current literature analyzing the molecular basis of epigenetic memory in mammals, with a focus on the mechanisms by which transcriptionally repressive chromatin modifications such as methylation of DNA and histone H3 are propagated through mitotic cell divisions. The emerging picture suggests that cellular memory is supported by an epigenetic cycle in which reversible activities carried out by epigenetic regulators in coordination with cell cycle transition create a multiphasic system that can accommodate both maintenance of cell identity and cell differentiation in proliferating stem cell populations.

The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Regulation of adipogenesis by histone methyltransferases.

Epigenetic regulation is a critical component of lineage determination. Adipogenesis is the process through which uncommitted stem cells or adipogenic precursor cells differentiate into adipocytes, the most abundant cell type of the adipose tissue. Studies examining chromatin modification during adipogenesis have provided further understanding of the molecular blueprint that controls the onset of adipogenic differentiation. Unlike histone acetylation, histone methylation has context dependent effects on the activity of a transcribed region of DNA, with individual or combined marks on different histone residues providing distinct signals for gene expression. Over half of the 42 histone methyltransferases identified in mammalian cells have been investigated in their role during adipogenesis, but across the large body of literature available, there is a lack of clarity over potential correlations or emerging patterns among the different players. In this review, we will summarize important findings from studies published in the past 15 years that have investigated the role of histone methyltransferases during adipogenesis, including both protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). We further reveal that PRMT1/4/5, H3K4 KMTs (MLL1, MLL3, MLL4, SMYD2 and SET7/9) and H3K27 KMTs (EZH2) all play positive roles during adipogenesis, while PRMT6/7 and H3K9 KMTs (G9a, SUV39H1, SUV39H2, and SETDB1) play negative roles during adipogenesis.

Histone methyltransferase SUV39H2 regulates apoptosis and chemosensitivity in prostate cancer through AKT/FOXO signaling pathway.

Prostate cancer (PCa) is one of the most common malignant tumors that exhibit both chemoresistance and recurrence. SUV39H2 is highly expressed in many types of human tumors, but its role in the development and progression of PCa has never been clarified. The aim of this study is to elucidate the role of SUV39H2 in the development and progression of PCa, its association with the AKT/FOXO signaling pathway, and its potential implications for PCa diagnosis and treatment. SUV39H2 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype tissue expression pan-cancer data. The TCGA database was evaluated for SUV39H2 enrichment and its correlation to immune cell infiltration. SUV39H2 levels in PCa tissues and control tissues were determined in 30 patients using qPCR and IHC. Clinical relevance was assessed via The Cancer Genome Atlas (TCGA). In vitro assessments including colony formation assays, Western Blot analysis, CCK-8 assays, and flow cytometry were utilized to establish SUV39H2's contribution to PCa cell growth. The influence of SUV39H2 on PC3 and DU145 cell proliferation was assessed through a cell line-derived xenograft model. Sphere formation assays and qPCR were employed to delineate SUV39H2's role in PCa stemness and chemosensitivity. In vitro macrophage polarization assays provided insights into SUV39H2's association with M2 macrophages, while enrichment analysis shed light on its role in FOXO signaling. PCa tissues expressed higher levels of SUV39H2 than normal tissues. By knocking down SUV39H2, PCa cells were made more chemosensitive to docetaxel and cell proliferation and stemness were inhibited. Additionally, SUV39H2 knockdown significantly inhibited in vivo PCa cell growth and inhibited the polarization of macrophages. Furthermore, SUV39H2 was found to regulate AKT/FOXO signaling by increasing Akt and FOXO3a phosphorylation. Our findings highlight SUV39H2's role in PCa cell apoptosis and chemosensitivity mainly by regulating the AKT/FOXO signaling pathway and suggest that SUV39H2 could be a potential target for PCa diagnosis and treatment.

ULTRAPETALAs in action: Unraveling their role in root development.

The epigenetic complex Trithorax (TrxG) regulates gene transcription through post-translational histone modifications and is involved in a wide range of developmental processes. ULTRAPETALA1 (ULT1) is a SAND domain plant-exclusive TrxG protein that regulates the H3K4me3 active mark to counteract PcG repression. ULT1 has been identified to be involved in multiple tissue-specific processes. In the Arabidopsis root, ULT1 is required to maintain the stem cell niche, a role that is independent of the histone methyltransferase ATX1. Here we show the contribution of ULT2 in the maintenance of root stem cell niche. We also analyzed the gene expression in the ult1, ult2, and ult1ult2 mutants, evidencing three ways in which ULT1 and ULT2 regulate gene expression, one of them, where ULT1 or ULT2 regulate specific genes each, another where ULT1 and ULT2 act redundantly, as well as a regulation that requires of ULT1 and ULT2 together, supporting a coregulation, never reported. Furthermore, we also evidenced the participation of ULT1 in transcriptional repression synergically with CLF, a key histone methyltransferase of PcG.

The Wnt-pathway corepressor TLE3 interacts with the histone methyltransferase KMT1A to inhibit differentiation in Rhabdomyosarcoma.

Rhabdomyosarcoma tumor cells resemble differentiating skeletal muscle cells, which unlike normal muscle cells, fail to undergo terminal differentiation, underlying their proliferative and metastatic properties. We identify the corepressor TLE3 as a key regulator of rhabdomyosarcoma tumorigenesis by inhibiting the Wnt-pathway. Loss of TLE3 function leads to Wnt-pathway activation, reduced proliferation, decreased migration, and enhanced differentiation in rhabdomyosarcoma cells. Muscle-specific TLE3-knockout results in enhanced expression of terminal myogenic differentiation markers during normal mouse development. TLE3-knockout rhabdomyosarcoma cell xenografts result in significantly smaller tumors characterized by reduced proliferation, increased apoptosis and enhanced differentiation. We demonstrate that TLE3 interacts with and recruits the histone methyltransferase KMT1A, leading to repression of target gene activation and inhibition of differentiation in rhabdomyosarcoma. A combination drug therapy regime to promote Wnt-pathway activation by the small molecule BIO and inhibit KMT1A by the drug chaetocin led to significantly reduced tumor volume, decreased proliferation, increased expression of differentiation markers and increased survival in rhabdomyosarcoma tumor-bearing mice. Thus, TLE3, the Wnt-pathway and KMT1A are excellent drug targets which can be exploited for treating rhabdomyosarcoma tumors.

Epigenetic Causes of Overgrowth Syndromes.

Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.

Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1.

BACKGROUND: Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear. METHODS: We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed. RESULTS: The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D. CONCLUSIONS: KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.