Yayan Feng

Background: Transposable elements (TEs), known as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. However, transposable element (TE) dysregulation of quantitative trait loci (QTL) has not been well‐characterized in human disease, such as Alzheimer’s disease (AD).Method: In this study, we present the first catalog of transposable element quantitative trait loci (teQTLs) in human brains. By leveraging large‐scale RNA‐sequencing (RNA‐seq), whole‐genome sequencing (WGS), and various QTL data (xQTL) from three brain biobanks with Alzheimer’s disease (AD), we comprehensively characterize TE dysregulation across diverse AD pathobiology, including Tau, amyloid beta, APOE genotypes, and sex differences. We further integrate different types of QTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls to identify AD likely causal genes regulated by brain teQTLs through colocalization analysis. Regulatory roles of brain teQTLs are dissected via long‐range cell type‐specific enhancer‐promoter chromatin interaction maps.Result: Joint‐analysis of WGS and RNA‐seq data identified 77,335 genome‐wide significant TE expression QTLs (teQTLs) in human AD brains. Colocalization analysis of teQTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls identified key AD likely causal genes regulated by brain teQTLs. This identified new AD risk genes, including complement C1q tumor necrosis factor‐related protein 4 (C1QTNF4) and farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). A TE from Plat_L3 subfamily (chr11: 47605296‐47605575) suppressed expression of C1QTNF4 (its nearest gene) via long‐range enhancer‐promoter chromatin interaction in neurons. We identified that a TE from AluSz6 subfamily (chr8: 11834847‐11835127) increased expression of FDFT1 (its nearest gene) via microglia‐specific long‐range chromatin looping. Expression perturbation of FDFT1 and C1QTNF4 were significantly correlated with Braak staging score of AD patients. We further identified that individuals with AD risk allele APOE4 displayed elevated expression of AluSz6 and FDFT1 in patient induced pluripotent stem cells (iPSC)‐derived microglia and superior frontal gyrus (SFG) microglia compared to APOE3 individuals.Conclusion: These findings demonstrate widespread TE dysregulation in human brains and teQTLs offer a useful QTL analytic approach to identify AD risk genes and other complex diseases if broadly applied.

Genome assemblies provide a powerful basis of comparative multi-omics analyses that offer insight into parasite pathogenicity, host-parasite interactions, and invasion biology. As a unique intracellular nematode, Trichinella consists of two clades, encapsulated and non-encapsulated. Genomic correlation of the distinct differences between the two clades is still unclear. Here, we report an annotated draft reference genome of non-encapsulated Trichinella, T. pseudospiralis, and perform comparative multi-omics analyses with encapsulated T. spiralis. Genome and methylome analyses indicate that, during Trichinella evolution, the two clades of Trichinella exhibit differential expansion and methylation of parasitism-related multi-copy gene families, especially for the DNase II members of the phospholipase D superfamily and Glutathione S-transferases. Further, methylome and transcriptome analyses revealed divergent key excretory/secretory (E/S) genes between the two clades. Among these key E/S genes, TP12446 is significantly more expressed across three life stages in T. pseudospiralis. Overexpression of TP12446 in the mouse C2C12 skeletal muscle cell line could induce inhibition of myotube formation and differentiation, further indicating its key role in parasitism of T. pseudospiralis. This multi-omics study provides a foundation for further elucidation of the mechanism of nurse cell formation and immunoevasion, as well as the identification of pharmacological and diagnostic targets of trichinellosis.

β-Catenin recruits BRD4 and other coregulators to protect pluripotency gene transcription against network perturbation.

The bicolor Asiatic hybrid lily cultivar ‘Tiny Padhye’ is an attractive variety because of its unique color pattern. During its bicolor tepal development, the upper tepals undergo a rapid color change from green to white, while the tepal bases change from green to purple. However, the molecular mechanisms underlying these changes remain largely uncharacterized. To systematically investigate the dynamics of the lily bicolor tepal transcriptome during development, we generated 15 RNA-seq libraries from the upper tepals (S2-U) and basal tepals (S1-D, S2-D, S3-D, and S4-D) of Lilium ‘Tiny Padhye’. Utilizing the Illumina platform, a total of 295,787 unigenes were obtained from 713.12 million high-quality paired-end reads. A total of 16,182 unigenes were identified as differentially expressed genes during tepal development. Using Kyoto Encyclopedia of Genes and Genomes pathway analysis, candidate genes involved in the anthocyanin biosynthetic pathway (61 unigenes) and chlorophyll metabolic pathway (106 unigenes) were identified. Further analyses showed that most anthocyanin biosynthesis genes were transcribed coordinately in the tepal bases, but not in the upper tepals, suggesting that the bicolor trait of ‘Tiny Padhye’ tepals is caused by the transcriptional regulation of anthocyanin biosynthetic genes. Meanwhile, the high expression level of chlorophyll degradation genes and low expression level of chlorophyll biosynthetic genes resulted in the absence of chlorophylls from ‘Tiny Padhye’ tepals after flowering. Transcription factors putatively involved in the anthocyanin biosynthetic pathway and chlorophyll metabolism in lilies were identified using a weighted gene co-expression network analysis and their possible roles in lily bicolor tepal development were discussed. In conclusion, these extensive transcriptome data provide a platform for elucidating the molecular mechanisms of bicolor tepals in lilies and provide a basis for similar research in other closely related species.