Biology subjects

Siddappa, M.

Publications and source records attributed to Siddappa, M..

3 recordsLinked to original sources

bioRxiv2023

Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer

The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RAR{gamma}s ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RAR{gamma} complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking. Identifying the repertoire of miR-96 bound and regulated gene targets, including those recognition elements marked by m6A, revealed their significant enrichment in the RAR{gamma} complex. RAR{gamma} significantly enhanced the AR cistrome, particularly in active enhancers and super-enhancers, and overlapped with the binding of bookmarking factors. Furthermore, RAR{gamma} expression led to nucleosome-free chromatin enriched with H3K27ac, and significantly enhanced the AR cistrome in G2/M cells. RAR{gamma} functions also antagonized the transcriptional actions of the lineage master regulator ONECUT2. Similarly, gene programs regulated by either miR-96 or antagonized by RAR{gamma} were enriched in alternative lineages and more aggressive PCa phenotypes. Together these findings reveal an under-investigated role for RAR{gamma}, modulated by miR-96, to bookmark enhancer sites during mitosis. These sites are required by the AR to promote transcriptional competence, and emphasize luminal differentiation, while antagonizing ONECUT2.

cancer biology↗

bioRxiv2022

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined. ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients. ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

cancer biology↗

bioRxiv2020

Genome-wide analyses of transcription factors and co-regulators across seven cohorts identified reduced PPARGC1A expression as a driver of prostate cancer progression

Defining altered transcription factor (TF) and coregulators that are oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators. We addressed this challenge by using bootstrap approaches to test how expression, copy number alterations or mutation of TFs (n = 2662), coactivators (COA; n= 766); corepressor (COR; n = 599); mixed function coregulators (MIXED; n = 511) varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression ({rho} 0.4 to 0.55). Stringent expression filtering identified commonly altered TFs and coregulators including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1) in localized PCa. Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1 knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPAR{gamma} responses. GSEA analyses of the PGC1 transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1-dependent genes were overlapped with PGC1-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. Together these data demonstrate an approach to identify cancer-driver coregulators in cancer and that PGC1 expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

cancer biology↗