KMT2D-mediated H3K4me1 recruits YBX1 to facilitate triple-negative breast cancer progression through epigenetic activation of c-Myc.

BACKGROUND: Lysine methyltransferase 2D (KMT2D) mediates mono-methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D-mediated H3K4me1 mark modulates gene expression in triple-negative breast cancer (TNBC) progression is unresolved. METHODS AND RESULTS: We recognized Y-box-binding protein 1 (YBX1) as a "reader" of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP-seq and RNA-seq data indicated that YBX1 was co-localized with KMT2D-mediated H3K4me1 in the promoter regions of c-Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c-Myc and SENP1 in a KMT2D-dependent manner. CONCLUSION: Our results suggest that KMT2D-mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c-Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D-H3K4me1-YBX1 axis for TNBC treatment. HIGHLIGHTS: YBX1 is a KMT2D-mediated H3K4me1-binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c-Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c-Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

Brief Report: A Randomized Controlled Trial of a Digital Working Memory Intervention for Preschoolers Displaying ADHD Symptoms.

PURPOSE: This study aimed to investigate the effects of a self-paced digital working memory (WM) intervention on preschoolers with ADHD symptoms and explore the relation between WM and time perception (TP) through a randomized controlled trial. METHOD: Fifty preschoolers between four-to-six years of age (M = 4.93 years) were randomly assigned to three groups: a WM training group (WM; n = 14), a social-emotional (SE) training active control group (n = 15), and a waitlist control group (n = 21). Both the WM and SE groups received fifteen 10-min self-paced digital training sessions over five consecutive weeks. RESULTS: The digital WM training was effective in improving children's digit span performance compared to the waitlist control group only. Within-group comparisons across two time points indicated a near-significant improvement in numeration and trends of reduced ADHD symptoms and improved TP tasks in the WM group at the post-test, but between-group differences were not observed. CONCLUSION: The study showed limited effects of the WM training on preschoolers displaying ADHD symptoms. However, the results implied an association between working memory and time perception that awaits further investigation.

ALKBH5-mediated m6A demethylation of HS3ST3B1-IT1 prevents osteoarthritis progression.

HS3ST3B1-IT1 was identified as a downregulated long noncoding RNA in osteoarthritic cartilage. However, its roles and mechanisms in the pathogenesis of osteoarthritis (OA) are unclear. In this study, we demonstrated that the expressions of HS3ST3B1-IT1 and its maternal gene HS3ST3B1 were downregulated and positively correlated in osteoarthritic cartilage. Overexpression of HS3ST3B1-IT1 significantly increased chondrocyte viability, inhibited chondrocyte apoptosis, and upregulated extracellular matrix (ECM) proteins, whereas HS3ST3B1-IT1 knockdown had the opposite effects. In addition, HS3ST3B1-IT1 significantly ameliorated monosodium-iodoacetate-induced OA in vivo. Mechanistically, HS3ST3B1-IT1 upregulated HS3ST3B1 expression by blocking its ubiquitination-mediated degradation. Knockdown of HS3ST3B1 reversed the effects of HS3ST3B1-IT1 on chondrocyte viability, apoptosis, and ECM metabolism. AlkB homolog 5 (ALKBH5)-mediated N6-methyladenosine (m6A) demethylation stabilized HS3ST3B1-IT1 RNA. Together, our data revealed that ALKBH5-mediated upregulation of HS3ST3B1-IT1 suppressed OA progression by elevating HS3ST3B1 expression, suggesting that HS3ST3B1-IT1/HS3ST3B1 may serve as potential therapeutic targets for OA treatment.

METTL3-mediated m6A modification of IGFBP7-OT promotes osteoarthritis progression by regulating the DNMT1/DNMT3a-IGFBP7 axis.

Osteoarthritis (OA) is the most common degenerative disorder, affecting approximately half of the elderly population. In this study, we find that the expressions of long noncoding RNA (lncRNA) IGFBP7-OT and its maternal gene, IGFBP7, are upregulated and positively correlated in osteoarthritic cartilage. Overexpression of IGFBP7-OT significantly inhibits chondrocyte viability, promotes chondrocyte apoptosis, and reduces extracellular matrix components, whereas IGFBP7-OT knockdown has the opposite effects. IGFBP7-OT overexpression promotes cartilage degeneration and markedly aggravates the monosodium iodoacetate-induced OA phenotype in vivo. Further mechanistic research reveals that IGFBP7-OT promotes OA progression by upregulating IGFBP7 expression. Specifically, IGFBP7-OT suppresses the occupancy of DNMT1 and DNMT3a on the IGFBP7 promoter, thereby inhibiting methylation of the IGFBP7 promoter. The upregulation of IGFBP7-OT in OA is partially controlled by METTL3-mediated N6-methyladenosine (m6A) modification. Collectively, our findings reveal that m6A modification of IGFBP7-OT promotes OA progression by regulating the DNMT1/DNMT3a-IGFBP7 axis and provide a potential therapeutical target for OA treatment.

YTHDF2-mediated FGF14-AS2 decay promotes osteolytic metastasis of breast cancer by enhancing RUNX2 mRNA translation.

BACKGROUND: LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown. METHODS: TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan-Meier Plotter. RESULTS: We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS). CONCLUSIONS: FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.

Do Executive Dysfunction, Delay Aversion, and Time Perception Deficit Predict ADHD Symptoms and Early Academic Performance in Preschoolers.

Children with attention deficit/hyperactivity disorder (ADHD) are commonly observed to have learning difficulties. This study examined how three neuropsychological constructs-executive dysfunction, delay aversion, and time perception-were associated with ADHD symptoms and early academic performance in preschoolers at risk of ADHD. One hundred and thirty-one preschoolers (70 boys, 53%) aged 4 to 6 (M = 5.31 years) were assessed on their ADHD-related behaviors, neuropsychological functioning, word reading, and math abilities at two time points one year apart. Factor analysis indicated that inhibitory and attentional control deficit, delay aversion, and time perception/working memory deficit were three dissociable factors. Among the three factors, inhibitory and attentional control measured at Time 1 was the strongest predictor of ADHD symptoms at both Time 1 and Time 2. Time perception was closely related to working memory, and they predicted word reading and numeration across time most strongly among other neuropsychological constructs. Our findings suggested that inhibitory and attentional control, delay aversion, and time perception are dissociable neuropsychological deficits underlying ADHD symptoms in preschoolers. Poor time perception may serve as a marker for the early identification of preschoolers with potential learning problems, and a possible target of intervention for ADHD.

Validation of a developmental screening checklist for Chinese preschoolers in Hong Kong.

There are concerns about the cultural validity of applying developmental screeners developed and normed in Western countries to other sociocultural contexts. Given the scarcity of culturally validated developmental checklists for use among Chinese children, the Hong Kong Society for the Protection of Children (HKSPC) has developed the HKSPC Developmental Checklist (HKSPC-DC) for preschool teachers to identify children at risk of developmental delays through daily observation of children's functioning at school. This study explored the psychometric properties of the HKSPC-DC among 1183 preschool children aged 2-6 recruited from 14 nursery schools in Hong Kong. The HKSPC-DC showed excellent internal consistency, good interrater and test-retest reliabilities, and acceptable concurrent validity when correlated with the Taipei City Developmental Checklist for Preschoolers (Taipei II), which is the only screening instrument developed in a Chinese society and validated across 4- to 72-month-olds. The HKSPC-DC also showed good discriminatory power in identifying preschoolers potentially at risk of developmental delays. This screening tool may help facilitate early identification of children with developmental vulnerabilities in Chinese preschool populations.

Time Perception Deficits in Children and Adolescents with ADHD: A Meta-analysis.

OBJECTIVE: Prior studies have reported time perception impairment in children and adolescents with ADHD but the results were inconsistent. METHOD: The current meta-analysis reviews 27 empirical studies published in English after year 2000 that compared time perception competence among children and adolescents with and without ADHD. RESULTS: Results from 1620 participants with ADHD and 1249 healthy controls showed significant timing deficits in ADHD. Children/adolescents with ADHD perceived time less accurately (Hedges' g > 0.40), less precisely (Hedges' g = 0.66) and had higher tendency to overestimate time than their healthy counterparts. Moderator analyses indicated that the discrepancy of time perception between groups was not affected by the type of timing tasks nor the modality of stimuli used in the tasks. Nonetheless, results were moderated by age and gender. CONCLUSION: These findings may update current understanding of the underlying neuropsychological deficits in ADHD and provide insight for future research in clinical assessments and treatments for ADHD.

Functional CYP3A variants affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients.

The aim of this study was to identify novel genetic variants affecting tacrolimus trough blood concentrations. We analyzed the association between 58 single nucleotide polymorphisms (SNPs) across the CYP3A gene cluster and the log-transformed tacrolimus concentration/dose ratio (log (C0/D)) in 819 renal transplant recipients (Discovery cohort). Multivariate linear regression was used to test for associations between tacrolimus log (C0/D) and clinical factors. Luciferase reporter gene assays were used to evaluate the functions of select SNPs. Associations of putative functional SNPs with log (C0/D) were further tested in 631 renal transplant recipients (Replication cohort). Nine SNPs were significantly associated with tacrolimus log (C0/D) after adjustment for CYP3A5*3 and clinical factors. Dual luciferase reporter assays indicated that the rs4646450 G allele and rs3823812 T allele were significantly associated with increased normalized luciferase activity ratios (p < 0.01). Moreover, CYP3A7*2 was associated with higher TAC log(C0/D) in the group of CYP3A5 expressers. Age, serum creatinine and hematocrit were significantly associated with tacrolimus log (C0/D). CYP3A7*2, rs4646450, and rs3823812 are proposed as functional SNPs affecting tacrolimus trough blood concentrations in Chinese renal transplant recipients. Clinical factors also significantly affect tacrolimus metabolism.

Dimensional structure of the BRIEF2 and its relations with ADHD symptoms and task performance on executive functions in Chinese children.

This study examined the dimensional structure of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2) in a Chinese sample of children with attention-deficit/hyperactivity disorder (ADHD)-related concerns and the correlations of the BRIEF2 with the children's ADHD symptoms and their performance on executive function (EF) tasks. Participants were 339 Chinese children aged 6-15 (M = 9.18 years, SD = 2.33; boys: 78.2%) recruited from 35 schools in Hong Kong. The results from confirmatory factor analyses revealed the best fit for a three-factor nine-scale model compared to a two-factor or single-factor model. Significant correlations were found between the BRIEF2 parent and teacher forms for the Behavioral Regulation Index and Cognitive Regulation Index, but not for the Emotion Regulation Index. Associations between performance on an EF task and the rating of the corresponding subscale on the BRIEF2 purportedly measuring the same EF construct were not consistently observed. Lastly, the BRIEF2 showed good convergent validity with the ratings of ADHD symptoms on the Swanson, Nolan, and Pelham Rating Scale Version IV (SNAP-IV). This study provided plausibly the first evidence on the dimensional structure of the BRIEF2 Parent and Teacher Forms in an Asian sample and confirmed the factorial validity of the Chinese version of the BRIEF2.