In our initial findings, we used chromatin immunoprecipitation to show that p300 forms stabilized PIC assemblies with pol II at the promoters of rapidly responsive genes, that persist long after transcription has ended, leaving these genes in a bookmarked or poised state, for potentiated response to subsequent challenge. This form of transcriptional memory has broad implication for how cells and tissues might synchronize their response to environmental signaling especially during differentiation and development to produce stable changes in phenotypic attributes. This role of p300 in molecular memory is also consistent with the fact that the transcription cycle has several rate-limiting steps beginning with formation of the PIC and that multiple components of the PIC, like p300 could have a role in bridging transitions through these different steps by providing platforms for the assembly of phase specific components. The dynamic bookmarking that we described for p300 also led to the observation that p300 could form a staple complex at rapid response genes that enabled the entry of the eleven nineteen lysine rich leukemia factor (ELL), much earlier in the elongation phase than previously thought, to participate in the early escape of pol II from the transcription start site prior to entry into the pause site for subsequent transition to productive elongation by facilitating assembly of the fully competent elongation factor complex. This coupled with the reciprocal kinetics of CtBP recruitment to rapidly induced genes during the transcription cycle lead us to hypothesized that CtBP may indeed play a role in the transcription cycle by first blocking subsequent recruitment of elongation factors and then by recruiting repressive chromatin modifying complexes that reduce activity and eventually prime the genes for repression. These findings are support by the following findings from our lab: 1) We have defined that p300 plays a central role the control of primary genetic response in human cells. 2) We have made the first description of the process of dynamic bookmarking of endogenous genes by the p300-containing RNA polymerase II complexes. This defines a mechanism for molecular memory that may have a role in physiological responses as diverse as epithelial differentiation, drug resistance, drug addiction, immunological memory and cognitive memory. 3) By quantitative chromatin immunoprecipitation and genome-wide location analysis we found that p300 plays a role in the dynamic bookmarking of mitotic chromatin in manner that facilitates the transfer of molecular memory, encoded in formed transcriptional complexes at specific genes in the parental cells, to subsequent populations of progeny cells. Depletion of p300 results in disrupted formation of these complexes and reduced histone acetylation at specific genes of parental cell progeny. These findings implicate a major role for p300 in the stable propagation of epigenetic information to subsequent generation of cells. 4.) Genome-wide analysis of the p300 assembly in mammary epithelial cells show significant co-assembly of with CtBP at both enhancer and promoter regions. 5.) Gene depletion followed by gene expression and chromatin IP reveal that CtBP is recruit at the cessation of immediate early gene expression in a manner reciprocal to the recruitment of elongation factors (like ELL) at paused transcriptional complexes. 6.) In genome-wide location analysis we have found that the elongation factor eleven-nineteen lysine rich leukemia protein (ELL) assembles in the coding regions of numerous genes where it travels with the transcriptionally engaged and elongating RNA polymerase. 7.) Depletion of CtBP results in prolonged transcription at rapidly induced genes. 8.) Gene reactivation by DNA methylation inhibitors at silenced p300 and CtBP controlled genes reveal dynamic re-recruitment of pol II and p300 complexes. 9.) Re-recruitment of poll II and p300 to reactivated genes is associated with increased recruitment of CtBP. 10.) Reactivation of silenced p300 and CtBP controlled genes by DNA methylation inhibitors is potentiated by CtBP depletion. 11.) Depletion of CtBP blocks re-silencing of reactivated genes after removal of DNA methylation inhibitors. 12. CtBP depletion results in impair recruitment of PRC1 and PRC2 complexes to reactivated gene upon removal of DNA methylation inhibitor thus impairing gene silencing. 13.) ELL is required for both pause site entry and pausing release of RNA polymerase II. 14.) ELL containing complexes are targeted for regulation by both leukemogenic MLL fusion protein and the HTLV-1 Tax oncoprotein. 15.) We have successfully developed an antibody the recognizes ELL by immunoblot, immune-fluorescence, immune-peroxidase staining in human tissue sections, by ELISA and by chromatin immune-precipitation. 16.) Using this antibody in human tissues sections we find that ELL is highly enriched in differentiated tissues and expressed at lower levels in both low grade and high grade breast cancer patient samples. This is consistent with recent studies suggesting that ELL functions as a tumor suppressor. 17.) Genome-wide profiling of assembly of CtBP, and p300 at promoters and enhancer reveal significant overlap at estrogen receptor targeted genes and enhancers in addition to co-occupancy with putative pioneer transcription factors for ER chromatin association.
| Fufa, Temesgen D; Byun, Jung S; Wakano, Clay et al. (2015) The Tax oncogene enhances ELL incorporation into p300 and P-TEFb containing protein complexes to activate transcription. Biochem Biophys Res Commun 465:5-11 |
| Wong, Madeline M; Byun, Jung S; Sacta, Maria et al. (2014) Promoter-bound p300 complexes facilitate post-mitotic transmission of transcriptional memory. PLoS One 9:e99989 |
| Byun, Jung S; Gardner, Kevin (2013) C-Terminal Binding Protein: A Molecular Link between Metabolic Imbalance and Epigenetic Regulation in Breast Cancer. Int J Cell Biol 2013:647975 |
| De Luca, P; Moiola, C P; Zalazar, F et al. (2013) BRCA1 and p53 regulate critical prostate cancer pathways. Prostate Cancer Prostatic Dis 16:233-8 |
| Byun, Jung S; Fufa, Temesgen D; Wakano, Clay et al. (2012) ELL facilitates RNA polymerase II pause site entry and release. Nat Commun 3:633 |
| Wakano, Clay; Byun, Jung S; Di, Li-Jun et al. (2012) The dual lives of bidirectional promoters. Biochim Biophys Acta 1819:688-93 |
| Li, Xiangzhi; Li, Li; Pandey, Ruchi et al. (2012) The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptional network. Cell Stem Cell 11:163-78 |
| De Siervi, Adriana; De Luca, Paola; Byun, Jung S et al. (2010) Transcriptional autoregulation by BRCA1. Cancer Res 70:532-42 |
| Moiola, Cristian; De Luca, Paola; Gardner, Kevin et al. (2010) Cyclin T1 overexpression induces malignant transformation and tumor growth. Cell Cycle 9:3119-26 |
| Byun, Jung S; Wong, Madeline M; Cui, Wenwu et al. (2009) Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes. Proc Natl Acad Sci U S A 106:19286-91 |
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