Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription

Beagrie, Robert A.; Pombo, Ana

doi:10.1002/bies.201600032

Cited by 41 publications

(40 citation statements)

References 123 publications

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“…Enhancers are DNA sequences comprised of clusters of binding sites for different TFs that activate expression of a gene, and by virtue of the TFs that they bind, they may act on different steps in transcription (Beagrie & Pombo 2016). At developmental genes it is common for a promoter to be activated by more than one enhancer in the same cells at the same time (Cannavò et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Gene Regulation through Kinetic Control of the Transcription Cycle

2017

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Cells decide when, where, and to what level to express their genes by “computing” information from transcription factors (TFs) binding to regulatory DNA. How is the information contained in multiple TF binding sites integrated to dictate the rate of transcription? The dominant conceptual and quantitative model is that TFs combinatorially recruit one another and RNA polymerase to the promoter by direct physical interactions. Here we develop a quantitative framework to explore kinetic control, an alternative model in which combinatorial gene regulation can result from TFs working on different kinetic steps of the transcription cycle. Kinetic control can generate a wide range of analog and Boolean computations without requiring the input TFs to be simultaneously bound to regulatory DNA. We propose experiments that will illuminate the role of kinetic control in transcription and discuss implications for deciphering the cis-regulatory “code”.

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Section: Discussionmentioning

confidence: 99%

Combinatorial Gene Regulation through Kinetic Control of the Transcription Cycle

2017

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“…Enhancers are regulatory regions that can locate on the linear genome quite far from their target genes and still contact them via chromatin looping that joins target genes and enhancers in 3D space [75] through the action of structural protein complexes comprising CTCF (CCCTC-binding factor), cohesin, and Mediator [76]. Similar to promoters, many enhancers operate in a cell-type specific and spatiotemporal manner during development.…”

Section: Polycomb Group Complexes In Embryonic Stem Cells Restrain Nementioning

confidence: 99%

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

et al. 2017

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Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene-and/or stage-specific, mechanisms to mediate spatiotemporal gene expression during central nervous system development. In the course of this, PcG proteins bind to various cis-regulatory sequences (e.g., promoters, enhancers or silencers) and coordinate, as well the interactions between distantly separated genomic regions to control chromatin function at different scales ranging from compaction of the linear chromatin to the formation of topological hubs. Recent findings show that PcG proteins are involved in switch-like changes in gene expression states of selected neural genes during the transition from multipotent to differentiating cells, and then to mature neurons. Beyond neurodevelopment, PcG proteins sustain mature neuronal function and viability, and prevent progressive neurodegeneration in mice. In support of this view, neuropathological findings from human neurodegenerative diseases point to altered PcG functions. Overall, improved insight into the multiplicity of PcG functions may advance our understanding of human neurodegenerative diseases and ultimately pave the way to new therapies.

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“…For example, the activator activity might depend on posttranslational modifications or the interaction with specific partners that are lacking in our system. Transactivation activity could also depend on promoter context [74] since many TFs depend on the position of the TF binding motifs within the promoter to activate transcription [75–77]. It is also possible that some of the predicted regulators act as repressors in plants.…”

Section: Discussionmentioning

confidence: 99%

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

et al. 2017

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BackgroundThe molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized.ResultsTo identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation. We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription.ConclusionsOur results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3853-9) contains supplementary material, which is available to authorized users.

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Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription

Abstract: Mechanisms of gene activation by metazoan enhancers: New insights and opportunities from high-throughput approachesBeagrie

Cited by 41 publications

References 123 publications

Combinatorial Gene Regulation through Kinetic Control of the Transcription Cycle

Combinatorial Gene Regulation through Kinetic Control of the Transcription Cycle

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

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