Observation of the possible magnetic correction above the Curie temperature in Cr2Si2Te6 single crystals.

Intrinsic magnetic semiconductors hold great promise in the fields of fundamental magnetization and spintronics. One such semiconductor is Cr2Si2Ti6 (CST), a quasi two-dimensional (2D) magnetic semiconductor with potential applications in future magnetic devices. However, the origin of ferromagnetism in CST remains a mystery. To investigate this, ac/dc susceptibility and electronic spin resonance (ESR) measurements were conducted. Based on ac susceptibility scaling, the critical temperature (TC) for the ferromagnetic (FM) to paramagnetic (PM) phase transition was found to be ∼32.5 K, with a critical exponent of δ = 6.7 from the critical isotherm, ß + γ = 1.72 from the temperature dependence of the crossover line, and γ = 1.43 from the temperature dependence of susceptibility along the same line. All critical exponents were found to be consistent with the dc magnetization scaling method. However, above and below TC, the origin of magnetism cannot be explained by a single theory. To explore the origin of abnormal magnetic critical behavior, ESR measurements were performed. Below T* ∼ 130 K, the ESR measurements revealed that the resonance field width (ΔH) tends to increase and decrease for the applied magnetic field H parallel and perpendicular to the c axis, respectively, indicating the onset of magnetic interaction even in the PM state. Meanwhile, the deviation from Curie-Weiss behavior below T* also confirmed the occurrence of magnetic correlation above the TC in CST. These observations suggest that the competition and cooperation among the direct and indirect interactions, the structural distortion and the van der Waals interaction at high temperature should be considered to investigate the origin of anomalous magnetism in CST. The present results provide valuable insights into the nature of ferromagnetism in 2D magnetic semiconductors.

Origin of the Anomalous Electrical Transports in Quasi-One-Dimensional Ta2NiSe7.

Exploration of exotic transport behavior is of great interest and importance for revealing the properties of the CDW phase of quasi-one-dimensional Ta2NiSe7. We report the anisotropic electrical transport properties of Ta2NiSe7 single crystals in the CDW phase. The anisotropic constant (γ = ρb/ρc) increased rapidly at TCDW = 60 K upon cooling. The results of the Hall resistivity show that both the concentrations and mobilities of carriers change abruptly at TCDW. The out-of-plane AMR exhibits C2 and C4 symmetry components while the in-plane AMR exhibits C2, C4, and C6 at the CDW state. The planar Hall effect is observed in Ta2NiSe7 at low temperature, which is suggested to originate from the anisotropic orbital magnetoresistance. The calculated results show that the Fermi surface of Ta2NiSe7 was slightly reconstructed due to the CDW transition. This work highlights the enhancement of Fermi surface anisotropy during CDW formation and provides a novel approach to study the CDW materials.

KDM4 Demethylases: Structure, Function, and Inhibitors.

KDM4 histone demethylases mainly catalyze the removal of methyl marks from H3K9 and H3K36 to epigenetically regulate chromatin structure and gene expression. KDM4 expression is strictly regulated to ensure proper function in a myriad of biological processes, including transcription, cellular proliferation and differentiation, DNA damage repair, immune response, and stem cell self-renewal. Aberrant expression of KDM4 demethylase has been documented in many types of blood and solid tumors, and thus, KDM4s represent promising therapeutic targets. In this chapter, we summarize the current knowledge of the structures and regulatory mechanisms of KDM4 proteins and our understanding of their alterations in human pathological processes with a focus on development and cancer. We also review the reported KDM4 inhibitors and discuss their potential as therapeutic agents.

A Model Combining Multi Branch Spectral-Temporal CNN, Efficient Channel Attention, and LightGBM For MI-BCI Classification.

Accurately decoding motor imagery (MI) brain-computer interface (BCI) tasks has remained a challenge for both neuroscience research and clinical diagnosis. Unfortunately, less subject information and low signal-to-noise ratio of MI electroencephalography (EEG) signals make it difficult to decode the movement intentions of users. In this study, we proposed an end-to-end deep learning model, a multi-branch spectral-temporal convolutional neural network with channel attention and LightGBM model (MBSTCNN-ECA-LightGBM), to decode MI-EEG tasks. We first constructed a multi branch CNN module to learn spectral-temporal domain features. Subsequently, we added an efficient channel attention mechanism module to obtain more discriminative features. Finally, LightGBM was applied to decode the MI multi-classification tasks. The within-subject cross-session training strategy was used to validate classification results. The experimental results showed that the model achieved an average accuracy of 86% on the two-class MI-BCI data and an average accuracy of 74% on the four-class MI-BCI data, which outperformed current state-of-the-art methods. The proposed MBSTCNN-ECA-LightGBM can efficiently decode the spectral and temporal domain information of EEG, improving the performance of MI-based BCIs.

A Self-Healing PVA-Linked Phytic Acid Hydrogel-Based Electrolyte for High-Performance Flexible Supercapacitors.

Flexible supercapacitors can be ideal flexible power sources for wearable electronics due to their ultra-high power density and high cycle life. In daily applications, wearable devices will inevitably cause damage or short circuit during bending, stretching, and compression. Therefore, it is necessary to develop proper energy storage devices to meet the requirements of various wearable electronic devices. Herein, Poly(vinyl alcohol) linked various content of phytic acid (PVA-PAx) hydrogels are synthesized with high transparency and high toughness by a one-step freeze-thaw method. The effects of different raw material ratios and agents on the ionic conductivity and mechanical properties of the hydrogel electrolyte are investigated. The PVA-PA21% with 2 M H2SO4 solution (PVA-PA21%-2 M H2SO4) shows a high ionic conductivity of 62.75 mS cm-1. Based on this, flexible supercapacitors fabricated with PVA-PA21%-2 M H2SO4 hydrogel present a high specific capacitance at 1 A g-1 after bending at 90° (64.8 F g-1) and for 30 times (67.3 F g-1), respectively. Moreover, the device shows energy densities of 13.5 Wh kg-1 and 14.0 Wh kg-1 at a power density of 300 W kg-1 after bending at 90° and for 30 times during 10,000 cycles. It provides inspiration for the design and development of electrolytes for related energy electrochemical devices.

Study on cooperative constraint zoning of water environment.

This study comprehensively considers two elements of water environmental sensitivity and pressure using the combination of qualitative analysis and quantitative calculation. And it puts forward the water environmental collaborative constraint zoning method and focuses on the construction of the water environmental collaborative constraint zoning evaluation index system using the fuzzy optimization programming model to determine the index weight. This study takes the Liaohe River Basin in Liaoning Province as a study area through two-dimensional quadrant analysis of water environmental sensitivity and pressure; it is divided into four types of areas: high-pressure and high-sensitivity area (HP-HS area), high-pressure and low-sensitivity area (HP-LS area), low-pressure and high-sensitivity area (LP-HS area) and low-pressure and low-sensitivity area (LP-LS area), respectively. The results show that the proportion of HP-HS area is 28.4%, the proportion of HP-LS area is 10.1%, the proportion of LP-HS area is 22.2% and the proportion of LP-LS area is 39.3%, respectively. The evaluation results are in line with the actual situation of the Liaohe River Basin in Liaoning Province. According to the results of different zoning, this research puts forward the optimization and adjustment scheme of industrial layout to achieve the comprehensive and coordinated sustainable development of population, economy, society, and environment in the study area. The research results also have been applied to the formulation of '14th Five-Year Plan' for water ecological environment protection of key river basins in Liaoning Province.

Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus.

SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2'-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Coupling of different plant functional group, soil, and litter nutrients in a natural secondary mixed forest in the Qinling Mountains, China.

Soil and litter play important roles in ecosystem nutrient storage and cycling, which both affect plant growth and ecosystem productivity. However, the potential linkages between soil and litter nutrient characteristics and nutrient characteristics of different plant functional groups (PFGs) remain unclear. In this study, we investigated the carbon (C), nitrogen (N), and phosphorus (P) concentrations and stoichiometric ratios in different organs of three PFGs (trees, shrubs, and herbs), litter, and soil in nine natural secondary mixed forests in the Qinling Mountains. Leaves N and P concentrations and N:P ratios, varied from 15.6 to 18.97 mg·g-1, 1.86 to 2.01 mg·g-1, and 7.34 to 8.72, were highest at the organ level, whereas the C:N and C:P values were lowest in leaves. At the PFG level, N and P concentrations of herbaceous were 1.23 to 3.69 and 1.42 to 1.93 times higher than those in same organs of woody species, while the N:P ratio was significantly lower in herb leaves than in tree and shrub leaves. Tree organs had significantly higher C concentrations and C:N and C:P ratios than shrub and herb organs. The leaf N:P ratios of all PFGs were less than 14, suggesting that plant growth was limited by N in the study region. The nutrient contents and stoichiometric ratios in plant organs had different degrees of linkages with those in litter and soil. Soil nutrient characteristics mainly affected (23.9 to 56.4%) the nutrient characteristics of the different PFGs, and litter nutrient characteristics also had important contributions (4.5 to 49.7%) to the nutrient characteristics of PFGs, showing the following order: herbs > trees > shrubs. Our results indicate that the functional difference in plant organs resulted in diverse nutrient concentrations; and varied nutrient connections exist among different ecosystem components. Furthermore, nutrient characteristics of litter and soil can together affect the nutrient characteristics of PFGs.

Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer.

Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1-WDR4 heterodimeric complex that might aid in understanding the key functional residues. Our results provide new information for further functional study of some METTL alterations in human cancer and might lead to the development of small inhibitors that target cancer-promoting METTLs.

Metagenomic characterization of lysine acetyltransferases in human cancer and their association with clinicopathologic features.

Lysine acetyltransferases (KATs) are a highly diverse group of epigenetic enzymes that play important roles in various cellular processes including transcription, signal transduction, and cellular metabolism. However, our knowledge of the genomic and transcriptomic alterations of KAT genes and their clinical significance in human cancer remains incomplete. We undertook a metagenomic analysis of 37 KATs in more than 10 000 cancer samples across 33 tumor types, focusing on breast cancer. We identified associations among recurrent genetic alteration, gene expression, clinicopathologic features, and patient survival. Loss-of-function analysis was carried out to examine which KAT has important roles in growth and viability of breast cancer cells. We identified that a subset of KAT genes, including NAA10, KAT6A, and CREBBP, have high frequencies of genomic amplification or mutation in a spectrum of human cancers. Importantly, we found that 3 KATs, NAA10, ACAT2, and BRD4, were highly expressed in the aggressive basal-like subtype, and their expression was significantly associated with disease-free survival. Furthermore, we showed that depletion of NAA10 inhibits basal-like breast cancer growth in vitro. Our findings provide a strong foundation for further mechanistic research and for developing therapies that target NAA10 or other KATs in human cancer.

Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression.

RNA methylation, catalysed by a set of RNA methyltransferases (RNMTs), modulates RNA structures, properties, and biological functions. RNMTs are increasingly documented to be dysregulated in various human diseases, particularly developmental disorders and cancer. However, the genomic and transcriptomic alterations of RNMTs, as well as their functional roles in human cancer, are limited. In this study, we utilized an unbiased approach to examine copy number alterations and mutation rates of 58 RNMTs in more than 10,000 clinical samples across 32 human cancer types. We also investigated these alterations and RNMT expression level as they related to clinical features such as tumour subtype, grade, and survival in a large cohort of tumour samples, focusing on breast cancer. Loss-of-function analysis was performed to examine RNMT candidates with important roles in growth and viability of breast cancer cells. We identified a subset of RNMTs, notably TRMT12, NSUN2, TARBP1, and FTSJ3, that were amplified or mutated in a subset of human cancers. Several RNMTs were significantly associated with breast cancer aggressiveness and poor prognosis. Loss-of-function analysis indicated FTSJ3, a 2'-O-Me methyltransferase, as a candidate RNMT with functional roles in promoting cancer growth and survival. A subset of RNMTs, like FTSJ3, represents promising novel targets for anticancer drug discovery. Our findings provide a framework for further study of the functional consequences of RNMT alterations in human cancer and for developing therapies that target cancer-promoting RNMTs in the future.

The Artificial Promoter rMdAG2I Confers Flower-specific Activity in Malus.

Genetic modifications of floral organs are important in the breeding of Malus species. Flower-specific promoters can be used to improve floral organs specifically, without affecting vegetative organs, and therefore developing such promoters is highly desirable. Here, we characterized two paralogs of the Arabidopsis thaliana gene AGAMOUS (AG) from Malus domestica (apple): MdAG1 and MdAG2. We then isolated the second-intron sequences for both genes, and created four artificial promoters by fusing each intron sequence to a minimal 35S promoter sequence in both the forward and reverse directions. When transferred into tobacco (Nicotiana benthamiana) by Agrobacterium tumefaciens-mediated stable transformation, one promoter, rMdAG2I, exhibited activity specifically in flowers, whereas the other three also showed detectable activity in vegetative organs. A test of the four promoters' activities in the ornamental species Malus micromalus by Agrobacterium-mediated transient transformation showed that, as in tobacco, only rMdAG2I exhibited a flower-specific expression pattern. Through particle bombardment transformation, we demonstrated that rMdAG2I also had flower-specific activity in the apple cultivar 'Golden Delicious'. The flower-specific promoter rMdAG2I, derived from M. domestica, thus has great potential for use in improving the floral characteristics of ornamental plants, especially the Malus species.

Profiles for long non-coding RNAs in ovarian granulosa cells from women with PCOS with or without hyperandrogenism.

RESEARCH QUESTION: What is the expression pattern of long non-coding RNAs (lncRNA) in ovarian granulosa cells of women with polycystic ovary syndrome (PCOS) with or without hyperandrogenism? DESIGN: Microarray screening of lncRNA was conducted in ovarian granulosa cells collected from women with PCOS with hyperandrogenism (PCOS-T) or without hyperandrogenism (PCOS-N) and control participants, with four samples in each group. This was followed by hierarchy clustering, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Several candidate lncRNA were randomly selected for quantitative polymerase chain reaction validation in another 54 patients. To predict the regulatory effect of lncRNA on hyperandrogenism, a co-expression network was plotted using differentially hexpressed lncRNA with statistical significance (≥ twofold; P < 0.05) in PCOS-T compared with PCOS-N. RESULTS: A total of 3000 and 1030 differentially expressed lncRNA (≥ twofold change) were detected in PCOS-T compared with control and PCOS-N, respectively. A total of 1361 differentially expressed lncRNA were detected in PCOS-N compared with controls. Corticotropin releasing hormone binding protein is consistently the up-regulated lncRNA with the highest fold-change in PCOS-T compared with either control or PCOS-N. Gene ontology and pathway analysis showed that dysregulated lncRNA in PCOS-T have a regulatory role in mitochondrial function by interacting with transcription factors such as YY1 and SIX5. CONCLUSIONS: The expression patterns of lncRNA in women with PCOS were ascertained by microarray. Many lncRNA were differentially expressed in PCOS-T compared with PCOS-N, suggesting that they may play a key role in steroid genesis and metabolism.

Genotranscriptomic meta-analysis of the CHD family chromatin remodelers in human cancers - initial evidence of an oncogenic role for CHD7.

Chromodomain helicase DNA binding proteins (CHDs) are characterized by N-terminal tandem chromodomains and a central adenosine triphosphate-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine-tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer.

HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer.

There are 18 lysine deacetylases, also known as histone deacetylases (HDACs), that remove acetyl groups from histone and non-histone proteins, thereby playing critical roles in numerous biological processes. In many human cancers, HDACs are dysregulated through mutation, altered expression, or inappropriate recruitment to certain loci. However, knowledge of the genomic and transcriptomic alterations and the clinical significance of most HDACs in breast cancer remain incomplete. We used TCGA and METABRIC datasets to perform comprehensive, integrated genomic and transcriptomic analyses of 18 HDAC genes in approximately 3000 primary breast cancers and identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found distinct patterns of copy number alteration and expression for each HDAC in breast cancer subtypes. We demonstrated that HDAC2 and SIRT7 were the most commonly amplified/overexpressed, and SIRT3 was most deleted/underexpressed, particularly in aggressive basal-like breast cancer. Overexpression of HDAC2 was significantly correlated with high tumor grade, positive lymph node status, and poor prognosis. The HDAC inhibitor mocetinostat showed anti-tumor effects in HDAC2-overexpressing basal-like breast cancer lines in vitro. Furthermore, HDAC2 expression was positively correlated with a set of DNA-damage response genes, notably RAD51. We revealed a potential mechanism by which HDAC2 regulates RAD51 expression-by indirect mediation through microRNAs, e.g., miR-182. HDAC inhibitors have emerged as a promising new class of multifunctional anticancer agents. Identifying which breast cancers or patients show HDAC deregulation that contributes to tumor development/progression might enable us to improve target cancer therapy.

Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer.

A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finger, MYND-type containing 8), ASXL1 (additional sex combs like 1) and CHD3 (chromodomain helicase DNA binding protein 3). Copy number increase and overexpression of ZMYND8 were more prevalent in Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. ZMYND8 was also involved in a positive feedback circuit of the estrogen receptor (ER) pathway, and the expression of ZMYND8 was repressed by the bromodomain and extra terminal (BET) inhibitor in breast cancer. Our findings suggest a promising avenue for future research-to focus on a subset of PHFs to better understand the molecular mechanisms and to identify therapeutic targets in breast cancer.

An integrated genomic analysis of Tudor domain-containing proteins identifies PHD finger protein 20-like 1 (PHF20L1) as a candidate oncogene in breast cancer.

Tudor domain-containing proteins (TDRDs), which recognize and bind to methyl-lysine/arginine residues on histones and non-histone proteins, play critical roles in regulating chromatin architecture, transcription, genomic stability, and RNA metabolism. Dysregulation of several TDRDs have been observed in various types of cancer. However, neither the genomic landscape nor clinical significance of TDRDs in breast cancer has been explored comprehensively. Here, we performed an integrated genomic and transcriptomic analysis of 41 TDRD genes in breast cancer (TCGA and METABRIC datasets) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. Among seven TDRDs that had the highest frequency (>10%) of gene amplification, the plant homeodomain finger protein 20-like 1 (PHF20L1) was the most commonly amplified (17.62%) TDRD gene in TCGA breast cancers. Different subtypes of breast cancer had different patterns of copy number and expression for each TDRD. Notably, amplification and overexpression of PHF20L1 were more prevalent in aggressive basal-like and Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. Furthermore, knockdown of PHF20L1 inhibited cell proliferation in PHF20L1-amplified breast cancer cell lines. PHF20L1 protein contains N-terminal Tudor and C-terminal plant homeodomain domains. Detailed characterization of PHF20L1 in breast cancer revealed that the Tudor domain likely plays a critical role in promoting cancer. Mechanistically, PHF20L1 might participate in regulating DNA methylation by stabilizing DNA methyltransferase 1 (DNMT1) protein in breast cancer. Thus, our results demonstrated the oncogenic potential of PHF20L1 and its association with poor prognostic parameters in breast cancer.

Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer.

Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome. Two KDMs, KDM2A and KDM5B, had the highest frequency of genetic amplification and overexpression. Furthermore, among the 24 KDM genes, KDM2A had the highest correlation between copy number and mRNA expression, and high mRNA levels of KDM2A were significantly associated with shorter survival of breast cancer patients. KDM2A has two isoforms: the long isoform is comprised of a JmjC domain, CXXC-zinc finger, PHD zinc finger, F-box, and the AMN1 protein domain; whereas the short isoform of KDM2A lacks the N-terminal JmjC domain but contains all other motifs. Detailed characterization of KDM2A in breast cancer revealed that the short isoform of KDM2A is more abundant than the long isoform at DNA, mRNA, and protein levels in a subset of breast cancers. Furthermore, our data indicate that the short isoform of KDM2A has oncogenic potential and functions as an oncogenic isoform in a subset of breast cancers. Taken together, our findings suggest that amplification and overexpression of the KDM2A short isoform is critical in breast cancer progression.

Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.

Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.