Compendium of human transcription factor effector domains

Soto, L; Li, Zhaorong; Santoso, Clarissa Stephanie; Berenson, Anna; Ho, Isabella; Shen, Vivian; Yuan, Samson; Bass, Juan I. Fuxman

doi:10.1016/j.molcel.2021.11.007

Cited by 79 publications

(105 citation statements)

References 91 publications

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“…The one known exception is IRF3, which is natively folded (Qin et al 2003). There are a handful of well studied repression domains, notably the KRAB and POZ/BTB domains, but aside from these two types, there are no good predictors of repression domains (Bintu et al 2016;Soto et al 2021). There is a rich body of work examining activation domain coactivator interactions with NMR; for example, p53, RelA, the ETV family, Hif1a, and CITED2 (Dyson and Wright 2016;Raj and Attardi 2017;Currie et al 2017;Berlow et al 2022) in human and Gcn4 and Gal4 in yeast (Brzovic et al 2011;Hahn and Young 2011;Tuttle et al 2021).…”

mentioning

confidence: 99%

Transcription factors perform a 2-step search of the nucleus

Staller

2022

Genetics

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Transcription factors regulate gene expression by binding to regulatory DNA and recruiting regulatory protein complexes. The DNA-binding and protein-binding functions of transcription factors are traditionally described as independent functions performed by modular protein domains. Here, I argue that genome binding can be a 2-part process with both DNA-binding and protein-binding steps, enabling transcription factors to perform a 2-step search of the nucleus to find their appropriate binding sites in a eukaryotic genome. I support this hypothesis with new and old results in the literature, discuss how this hypothesis parsimoniously resolves outstanding problems, and present testable predictions.

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mentioning

confidence: 99%

Transcription factors perform a 2-step search of the nucleus

Staller

2022

Genetics

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“…This is lower than the frequency found in the CtBP structured dehydrogenase domain, which is around 33% hydrophobic in the fly CtBP and human CtBP1. In comparison to experimentally validated repressor domains in the human proteome, which average around 45% hydrophobic content, the CtBP CTD also has much lower hydrophobicity (A and P residues were included and V excluded, compared to our method; Soto et al . 2022).…”

Section: Resultsmentioning

confidence: 93%

The cynosure of CtBP: evolution of a bilaterian transcriptional corepressor

Raicu

Kadiyala

Niblock

et al. 2022

Preprint

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Evolution of sequence-specific transcription factors clearly drives lineage-specific innovations, but less is known about how changes in the central transcriptional machinery may contribute to evolutionary transformations. In particular, transcriptional regulators are rich in intrinsically disordered regions that appear to be magnets for evolutionary innovation. The C-terminal Binding Protein (CtBP) is a transcriptional corepressor derived from an ancestral lineage of alpha hydroxyacid dehydrogenases; it is found in mammals and invertebrates, and features a core NAD-binding domain as well as an unstructured C-terminus (CTD) of unknown function. CtBP can act on promoters and enhancers to repress transcription through chromatin-linked mechanisms. Our comparative phylogenetic study shows that CtBP is a bilaterian innovation whose CTD of about 100 residues is present in almost all orthologs. CtBP CTDs contain conserved blocks of residues and retain a predicted disordered property, despite having variations in the primary sequence. Interestingly, the structure of the C-terminus has undergone radical transformation independently in certain lineages including flatworms and nematodes. Also contributing to CTD diversity is the production of myriad alternative RNA splicing products, including the production of short tailless forms of CtBP in Drosophila. Additional diversity stems from multiple gene duplications in vertebrates, where up to five CtBP orthologs have been observed. Vertebrate lineages show fewer major modifications in the unstructured CTD, possibly because gene regulatory constraints of the vertebrate body plan place specific constraints on this domain. Our study highlights the rich regulatory potential of this previously unstudied domain of a central transcriptional regulator.

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“…Disorder and/or conformational flexibility is a common characteristic of proteins and protein complexes that regulate transcription 34 . Mediator is a quintessential example of disorder and flexibility, having subunits that contain more intrinsically disordered regions (IDRs) than other protein complexes of comparable size 35 (Fig.…”

Section: Mediator Composition and Structurementioning

confidence: 99%

“…IDRs are common among eukaryotic proteins and are over-represented in transcription regulators 123 . A common feature among TFs is clusters of IDRs within their activation domains 34 . These IDR-containing activation domains directly bind Mediator and also allow TFs to undergo phase separation at physiologically relevant concentrations 36 , 124 .…”

Section: Mediator Function At Enhancersmentioning

confidence: 99%

The Mediator complex as a master regulator of transcription by RNA polymerase II

Richter

Nayak

Iwasa

et al. 2022

Nat Rev Mol Cell Biol

160

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The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo phase separation and to interact with a myriad of regulatory factors. In this Review, we discuss Mediator structure and function, with emphasis on recent cryogenic electron microscopy data of the 4.0-MDa transcription preinitiation complex. We further discuss how Mediator and sequence-specific DNA-binding transcription factors enable enhancer-dependent regulation of Pol II function at distal gene promoters, through the formation of molecular condensates (or transcription hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also discussed, in the context of transcription bursting. We propose a working model for Mediator function that combines experimental results and theoretical considerations related to enhancer–promoter interactions, which reconciles contradictory data regarding whether enhancer–promoter communication is direct or indirect. We conclude with a discussion of Mediator’s potential as a therapeutic target and of future research directions.

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Compendium of human transcription factor effector domains

Cited by 79 publications

References 91 publications

Transcription factors perform a 2-step search of the nucleus

Transcription factors perform a 2-step search of the nucleus

The cynosure of CtBP: evolution of a bilaterian transcriptional corepressor

The Mediator complex as a master regulator of transcription by RNA polymerase II

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