Biology subjects

Wu, S.-P.

Publications and source records attributed to Wu, S.-P..

3 recordsLinked to original sources

bioRxiv2019

Constitutive Expression of the Progesterone Receptor Isoforms Promotes Hormone-Dependent Development of Ovarian Neoplasms

Abnormal expression of the progesterone receptor (PGR) isoforms, PGRA and PGRB, is often observed in women with reproductive tract cancer. To assess the importance of the PGR isoform ratio in the maintenance of the healthy reproductive tract, mice with Cre recombinase- activated PGRA and PGRB transgenes were bred with the PGRCre mouse model to generate strains expressing either PGRA or PGRB in PGR positive tissues. The PGRB mice developed ovarian neoplasms at 23 weeks of age derived from ovarian luteal cells, while the PGRA expressing mice displayed a reduced frequency of tumor development. Transcriptomic analyses of the ovarian tumors revealed an enhanced AKT pathway signature, which is in agreement with expression changes found in human ovarian adenocarcinoma. Effective treatment with the PGR antagonist RU486 reduced tumor growth and the expression of cell cycle genes. We concluded that tumor growth and proliferation is hormone and PGR isoform dependent. Further analysis of the PGRB cistrome identified binding events of critical mitotic phase entry genes. This work suggests an intriguing mechanism whereby the expression of the PGR isoforms determines in vivo neoplasia through high-jacking of the cell cycle pathway.

cancer biology↗

bioRxiv2019

Association of SYNE2 variants in accelerating the progress of DYT1 early-onset isolated dystonia

DYT1 early-onset isolated dystonia (DYT1 dystonia), a rare autosomal dominant (AD) primary dystonia, is categorized as a monogenic disease. While it is a well-known AD inherited disease, the relatively low penetrance rate implicates potential modifiers in play for disease progression. In this report, an affected individual with TOR1A gene (c.907_909delGAG, p.E303del) variant, was identified along with three additional AD carriers in the family. Since we failed to find the second hit variant from TOR1A (D216H, F323_Y328del and F205I) and major binding proteins, including TOR1AIP1 and 2 or HSPA8 proteins, subsequent whole exome sequencing on the patient, the carriers and a non-carrier family member were performed to screen for candidate modifiers of TOR1A (E303del). The result reveals that this patient distinctly carries one copy of TOR1A gene (c.907_909delGAG, p.E303del) and one or two copy of SYNE2 gene (c.1721T>C, c.12001T>C, and c.12002G>A), encoding I574T, W4001R, and W4001Ter variants. We propose that these SYNE2 variants are linked to earlier disease onset in this patient by impacting the protein-protein interaction between TOR1A and SYNE2. Our study suggests SYNE2 gene maybe a culprit to lower the threshold for DYT1 dystonia progression and provides one novel gene target for further screening diagnosis of DYT1 dystonia.

genetics↗

bioRxiv2019

Dynamic Transcriptome, Accessible Genome and PGR Cistrome Profiles in the Human Myometrium

The myometrium undergoes structural and functional remodeling during pregnancy. We hypothesize that myometrial genomic elements alter correspondingly in preparation for parturition. Human myometrial tissues from nonpregnant (NP) and term pregnant (TP) human subjects were examined by RNAseq, ATACseq and PGR ChIPseq assays to profile transcriptome, assessible genome and PGR occupancy. NP and TP specimens exhibit 2890 differentially expressed genes, reflecting an increase of metabolic, inflammatory and PDGF signaling, among others, in adaptation to pregnancy. At the epigenome level, patterns of accessible genome change between NP and TP myometrium, leading to altered enrichment of binding motifs for hormone and muscle regulators such as the progesterone receptor (PGR), Kruppel-like factors and MEF2A transcription factors. PGR genome occupancy exhibits a significant difference between the two stages of the myometrium, concomitant with distinct transcriptomic profiles including genes such as ENO1, LHDA, and PLCL1 in the glycolytic and calcium signaling pathways. Over-representation of SRF, MYOD and STAT binding motifs in PGR occupying sites further suggests interactions between PGR and major muscle regulators for myometrial gene expression. In conclusion, changes in accessible genome and PGR occupancy are part of the myometrial remodeling process and may serve as mechanisms to formulate the state-specific transcriptome profiles.

genomics↗