Project description:The Tripartite motif-containing 28 (TRIM28) transcription factor is upregulated in high-grade prostate cancers and was recently proposed as a therapeutic target for castration-resistant prostate cancers. To study the role of TRIM28 in prostate cancer progression in vivo, we used a genetically engineered mouse model, combining prostate-specific Trim28 inactivation with inactivation of Trp53 and Pten. We analyzed the prostates using single cell RNA-Seq.
Project description:Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a novel E2F1-target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcription activation and genomic function of E2F1 independent of Rb status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and as such, RSK1 drives the TRIM28-E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1–TRIM28–E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.
Project description:Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. We set out to determine if adipose specific deletion of Trim28 led to changes in adipose tissue function and molecular phenotype. We performed transcriptomics analysis on adipose tissue taken from WT and adipose specific Trim28 KO mice to investigate their molecular phenotype, and to identify pathways altered in KO animals.
Project description:We studied CGNPs with conditional deletion of Eed using scRNA-seq. Eed was deleted in CGNPs by crossing Math1-Cre mice with Eed floxed mice. scRNA-seq seq was performed by Drop-seq. The results may be compared to our prior published data on scRNA-seq in normal CGNPs (GEO accession number GSE129730)
Project description:Single cell RNA-seq (scRNA-seq) from Trim28 ovary knockout and wildtype mice ovaries and testis to help elucidate the function of Trim28 in the adult mouse ovaries. The analysis revealed that loss of Trim28 in the adult mouse ovaries lead to a transcriptional repogramming of the Granulosa cells towards the Sertoli cell fate. Therefore, Trim28 has a function to maintain the adult ovarian cell identity
Project description:In this study, proteomic profiling of TRIM24 interactome in conjunction with shRNA screening of TRIM24 top-interactors nominated that TRIM28 is indispensable for TRIM24 protein stability. We showed that TRIM28 stabilizes TRIM24 against SPOP-mediated ubiquitination and degradation. TRIM28 promotes TRIM24 and AR transcription activity, androgen-dependent and -independent PCa growth. In addition, we demonstrated that TRIM28 level in high in advanced PCa, which drives TRIM24/AR transcription activity in a similar manner to SPOP mutation, which implies that TRIM28 potentially dictates the therapeutic outcome of TRIM24-targeted therapy.
Project description:Transcriptome analysis of lineage marked AR-deleted and wild type luminal prostate epithelial cells from prostates from 4 week old males, and bulk wild-type prostates from 3 week old male mice.
Project description:In this study, proteomic profiling of TRIM24 interactome in conjunction with shRNA screening of TRIM24 top-interactors nominated that TRIM28 is indispensable for TRIM24 protein stability. We showed that TRIM28 stabilizes TRIM24 against SPOP-mediated ubiquitination and degradation. TRIM28 promotes TRIM24 and AR transcription activity, androgen-dependent and -independent PCa growth. In addition, we demonstrated that TRIM28 level in high in advanced PCa, which drives TRIM24/AR transcription activity in a similar manner to SPOP mutation, which implies that TRIM28 potentially dictates the therapeutic outcome of TRIM24-targeted therapy.
Project description:We discovered that Trim28 genetic loss in the adult mouse leads to defective immature erythropoiesis in the bone marrow and consequently to anemia.We further found that TRIM28 controls erythropoiesis in a cell-autonomous manner by inducibly deleting Trim28 exclusively in hematopoietic cells. Finally, in the absence of TRIM28 we observed increased apoptosis as well as diminished expression of multiple erythroid transcription factors and heme biosynthetic enzymes in immature erythroid cells. Thus, TRIM28 is essential for the cell-autonomous development of immature erythroblasts in the bone marrow. To induce Cre recombinase from the Mx1Cre transgene, poly(I:C) was injected 5 times every other day. Mice were analyzed two weeks after completion of poly(I:C) administration. TRIM28 mutant mice generate two distinct types of immature erythroid cells; KOa, with 5-8% of the Trim28 gene remaining undeleted (still bearing 26% of residual mRNA), and KOb, with 1-4% of the gene remaining undeleted (and with 18% of mRNA remaining).