Cell Cycle Genes Are the Evolutionarily Conserved Targets of the E2F4 Transcription Factor

Conboy, Caitlin B.; Spyrou, Christiana; Thorne, Natalie; Wade, Elizabeth J.; Barbosa‐Morais, Nuno L.; Wilson, Michael D.; Bhattacharjee, Arindam; Young, Richard A.; Tavaré, Simon; Lees, Jacqueline A.; Odom, Duncan T.

doi:10.1371/journal.pone.0001061

Cited by 53 publications

(51 citation statements)

References 40 publications

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“…The occupancy of E1A at the MCM4 promoter was quite different from what we observed with the PCNA promoter. Unlike at the PCNA promoter, E2F4 was not previously reported to be present at the MCM4 promoter (7,9,27). During infection with virus expressing E1A 13S alone (pm975), E1A was present at the MCM4 promoter at a relatively high level (ϳ8% of the input; Fig.…”

Section: Vol 85 2011mentioning

confidence: 80%

Adenovirus E1A Directly Targets the E2F/DP-1 Complex

Pelka

Miller

Cecchini

et al. 2011

J Virol

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Deregulation of the cell cycle is of paramount importance during adenovirus infection. Adenovirus normally infects quiescent cells and must initiate the cell cycle in order to propagate itself. The pRb family of proteins controls entry into the cell cycle by interacting with and repressing transcriptional activation by the E2F transcription factors. The viral E1A proteins indirectly activate E2F-dependent transcription and cell cycle entry, in part, by interacting with pRb and family members to free the E2Fs. We report here that an E1A 13S isoform can unexpectedly activate E2F-responsive gene expression independently of binding to the pRb family of proteins. We demonstrate that E1A binds to E2F/DP-1 complexes through a direct interaction with DP-1. E1A appears to utilize this binding to recruit itself to E2F-regulated promoters, and this allows the E1A 13S protein, but not the E1A 12S protein, to activate transcription independently of interaction with pRb. Importantly, expression of E1A 13S, but not E1A 12S, led to significant enhancement of E2F4 occupancy of E2F sites of two E2F-regulated promoters. These observations identify a novel mechanism by which adenovirus deregulates the cell cycle and suggest that E1A 13S may selectively activate a subset of E2F-regulated cellular genes during infection.

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Section: Vol 85 2011mentioning

confidence: 80%

Adenovirus E1A Directly Targets the E2F/DP-1 Complex

Pelka

Miller

Cecchini

et al. 2011

J Virol

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“…This means that considerable differences in the biochemical pathways regulated by the transcription factors analysed are to be expected. Indeed, when analysing the Gene Ontology [55] categories that are enriched in different gene sets, species-specific gene targets correspond to novel functions regulated by the transcription factor under study [14,15,20,23]. Tuch et al [15] found that the transcription factor Mcm1 bound a conserved set of only 12 genes in S. cerevisiae, Kluyveromyces lactis and C. albicans, and there was enrichment for functional terms related to cell cycle and mating type.…”

Section: (C) Binding Event Turnover and Differences In Biochemical Pamentioning

confidence: 99%

Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution

Sakabe

Nóbrega

2013

Phil. Trans. R. Soc. B

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The complex expression patterns observed for many genes are often regulated by distal transcription enhancers. Changes in the nucleotide sequences of enhancers may therefore lead to changes in gene expression, representing a central mechanism by which organisms evolve. With the development of the experimental technique of chromatin immunoprecipitation (ChIP), in which discrete regions of the genome bound by specific proteins can be identified, it is now possible to identify transcription factor binding events (putative cis -regulatory elements) in entire genomes. Comparing protein–DNA binding maps allows us, for the first time, to attempt to identify regulatory differences and infer global patterns of change in gene expression across species. Here, we review studies that used genome-wide ChIP to study the evolution of enhancers. The trend is one of high divergence of cis -regulatory elements between species, possibly compensated by extensive creation and loss of regulatory elements and rewiring of their target genes. We speculate on the meaning of the differences observed and discuss that although ChIP experiments identify the biochemical event of protein–DNA interaction, it cannot determine whether the event results in a biological function, and therefore more studies are required to establish the effect of divergence of binding events on species-specific gene expression.

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“…Understanding the full regulatory potential of the cell cycle machinery in the brain therefore necessitates an appreciation of the repertoire of E2f target genes in NPCs. Genome-wide targets have been reported for E2f4 (and E2f1) in a number of immortalized and transformed cell lines, 20,22,23 and for E2f3 in immortal mouse myoblasts, myotubes and embryonic fibroblasts. 24,25 E2f targets have, however, not been identified on a genome-wide level in any neural cells, nor in any primary cell types.…”

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confidence: 99%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

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Cell Cycle Genes Are the Evolutionarily Conserved Targets of the E2F4 Transcription Factor

Cited by 53 publications

References 40 publications

Adenovirus E1A Directly Targets the E2F/DP-1 Complex

Adenovirus E1A Directly Targets the E2F/DP-1 Complex

Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution

Tissue-specific targeting of cell fate regulatory genes by E2f factors

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