Dissecting the effects of METTL3 on alternative splicing in prostate cancer

Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker

A reference-grade wild soybean genome

Wild relatives of crop plants are invaluable germplasm for genetic improvement. Here, Xie et al. report a reference-grade wild soybean genome and show that it can be used to identify structural variation and refine quantitative trait loci

A reference-grade wild soybean genome

Efficient crop improvement depends on the application of accurate genetic information contained in diverse germplasm resources. Here we report a reference-grade genome of wild soybean accession W05, with a final assembled genome size of 1013.2 Mb and a contig N50 of 3.3 Mb. The analytical power of the W05 genome is demonstrated by several examples. First, we identify an inversion at the locus determining seed coat color during domestication. Second, a translocation event between chromosomes 11 and 13 of some genotypes is shown to interfere with the assignment of QTLs. Third, we find a region containing copy number variations of the Kunitz trypsin inhibitor (KTI) genes. Such findings illustrate the power of this assembly in the analysis of large structural variations in soybean germplasm collections. The wild soybean genome assembly has wide applications in comparative genomic and evolutionary studies, as well as in crop breeding and improvement programs

“And this one’s juuust right!”: Prosody Predicts Reading Comprehension in Hong Kong Chinese-English Bilingual Children

This study examined the development of prosodic reading and its within- and cross-language contributions to reading comprehension among 121 Cantonese-English bilingual second-graders (aged 7 years, 70 girls) in 2015, and 52 of them as third-graders in 2016. Spectrographic analysis of their reading of one Chinese and one English passage revealed both cross-language similarities and language-specific differences in the use of pitch and pause when producing syntactically complex sentences. Wh question pitch contours emerged as the most robust predictor of reading comprehension across Chinese (r = .359) and English (r = -.457). A crossover effect occurred from Cantonese pitch to English reading comprehension (r = -.169). These results support the prosodic catalysing hypothesis, indicating the role of pitch in reading comprehension

The roles of prosody in Chinese-English reading comprehension

Background: Despite being an essential component of children’s oral reading fluency, prosodic reading, which involves expressive changes in pitch patterns and pause durations, has not been explored in Cantonese-English bilingual children, whose first language (L1) is tonal, non-alphabetic, and whose second language (L2) is non-tonal, alphabetic. Aims: This study examined the development of prosodic reading and its within- and cross-language associations with reading comprehension among Cantonese-English bilingual children from second to third grade. Sample: One hundred and twenty-one 7-to 8-year-old Cantonese-English bilingual children completed initial testing in grade 2, with 52 tested in grade 3. Methods: Prosodic reading was assessed using one Chinese and one English passage, each comprising six types of syntactic structures: declaratives, clause-final commas, yes-no questions, wh- questions, complex adjectival phrases, and quotatives. Word-reading efficiency, oral passage-reading fluency, and reading comprehension in Chinese and English were also measured. Results: Spectrographic analyses revealed that these children were aware of language-independent functions and language-specific manifestations of pitch and pause cues within and across their L1 Chinese and L2 English. Wh question pitch contours emerged as the most robust link to reading comprehension across both languages, while a crossover effect occurred from Cantonese pitch to English reading comprehension. Shorter pauses for English declarative quotative sentences and phrase-final commas were concurrently associated with greater English reading comprehension. Conclusions: These findings are interpreted within a new reading framework, the Prosodic Catalysing Hypothesis (PCH), which proposes that pitch and pause production can bridge prosody and syntax to facilitate reading comprehension

Single-Nucleotide Variations, Insertions/Deletions and Copy Number Variations in Myelodysplastic Syndrome during Disease Progression Revealed by a Single-Cell DNA Sequencing Platform

Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective hematopoiesis, cytopenia, dysplasia, and clonal instability, leading to leukemic transformation. Hypomethylating agents are the mainstay of treatment in higher-risk MDS. However, treatment resistance and disease transformation into acute myeloid leukemia (AML) is observed in the majority of patients and is indicative of a dismal outcome. The residual cell clones resistant to therapy or cell clones acquiring new genetic aberrations are two of the key events responsible for drug resistance. Bulk tumor sequencing often fails to detect these rare subclones that confer resistance to therapy. In this study, we employed a single-cell DNA (sc-DNA) sequencing approach to study the clonal heterogeneity and clonal evolution in two MDS patients refractory to HMA. In both patients, different single nucleotide variations (SNVs) or insertions and deletions (INDELs) were detected with bulk tumor sequencing. Rare cell clones with mutations that are undetectable by bulk tumor sequencing were detected by sc-DNA sequencing. In addition to SNVs and short INDELs, this study also revealed the presence of a clonal copy number loss of DNMT3A, TET2, and GATA2 as standalone events or in association with the small SNVs or INDELs detected during HMA resistance and disease progression

Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents

In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in azacitidine-resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents

Comparative Genomics Reveals Insights into the Divergent Evolution of Astigmatic Mites and Household Pest Adaptations.

10.1093/molbev/msac097Mol Biol Evol395msac097