The molecular grammar of protein disorder guiding genome-binding locations

Jonas, Felix; Carmi, Miri; Krupkin, Beniamin; Steinberger, Joseph; Brodsky, Sagie; Jana, Tamar; Barkai, Naama

doi:10.1093/nar/gkad184

Cited by 16 publications

(15 citation statements)

References 89 publications

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“…First, activation domains (ADs) that recruit coactivators to induce gene expression reside inside such regions ( 7–14 ). Second, IDRs can complement the DBD in directing TF binding preferences along genomes ( 5 , 6 , 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, different functions were attributed to common IDR design features. For example, studying Msn2, we found that the spreading of hydrophobic residues within an otherwise disordered sequence is the key IDR-design feature underlying its role in directing binding preferences ( 16 ). Others have reported similar features defining transcription activation domains ( 10–14 ), and additional work associated these same patterns with phase separation and formation of protein condensates ( 23–25 ).…”

Section: Introductionmentioning

confidence: 99%

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Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

Mindel,

Brodsky,

Cohen

et al. 2023

Nucleic Acids Research

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Intrinsically disordered regions (IDRs) are abundant in eukaryotic proteins, but their sequence-function relationship remains poorly understood. IDRs of transcription factors (TFs) can direct promoter selection and recruit coactivators, as shown for the budding yeast TF Msn2. To examine how IDRs encode both these functions, we compared genomic binding specificity, coactivator recruitment, and gene induction amongst a large set of designed Msn2-IDR mutants. We find that both functions depend on multiple regions across the > 600AA IDR. Yet, transcription activity was readily disrupted by mutations that showed no effect on the Msn2 binding specificity. Our data attribute this differential sensitivity to the integration of a relaxed, composition-based code directing binding specificity with a more stringent, motif-based code controlling the recruitment of coactivators and transcription activity. Therefore, Msn2 utilizes interwoven sequence grammars for encoding multiple functions, suggesting a new IDR design paradigm of potentially general use.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

Mindel,

Brodsky,

Cohen

et al. 2023

Nucleic Acids Research

Self Cite

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“…We, however, did not find a similar contribution from the negatively charged N-terminal extension. Certainly, nature has established multiple modes of fine-tuning DNA recognition through IDRs 71-73 , including roles for hydrophobic sequences as recently shown by Jonas et al 74 .…”

Section: Discussionmentioning

confidence: 99%

“…Certainly, nature has established multiple modes of fine-tuning DNA recognition through IDRs [71][72][73] , including roles for hydrophobic sequences as recently shown by Jonas et al 74 .…”

Section: Discussionmentioning

confidence: 99%

Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

von Ehr,

Oberstrass,

Yazgan

et al. 2024

Preprint

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AT-rich interacting domain (ARID)-containing proteins, Arids, are a heterogeneous DNA-binding protein family involved in transcription regulation and chromatin processing. For the member Arid5a, no exact DNA-binding preference has been experimentally defined so far. Additionally, the protein binds to mRNA motifs for transcript stabilization, supposedly through the DNA-binding ARID domain. To date, however, no unbiased RNA motif definition and clear dissection of nucleic acid-binding through the ARID domain have been undertaken. Using NMR-centered biochemistry, we here define the Arid5a DNA preference. Further, high-throughput in vitro binding (RBNS) reveals a consensus RNA-binding motif engaged by the core ARID domain. Finally, transcriptome-wide binding (iCLIP2) reveals that Arid5a has a weak preference for (A)U-rich regions in pre-mRNA transcripts of factors related to RNA processing. We find that the intrinsically disordered regions (IDR) flanking the ARID domain modulate the specificity and affinity of DNA-binding, while they appear crucial for RNA interactions. Ultimately, our data suggest that Arid5a uses its extended ARID domain for bi-functional gene regulation and that the involvement of IDR extensions is a more general feature of Arids in interacting with different nucleic acids at the chromatin-mRNA interface.

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“…For example, these regions can harbor important functions such as mediating protein-protein interactions [21], providing structural components needed to remodel chromatin [22], modifying DNA binding [23], and facilitating cooperative interactions with other transcriptional regulators [24,25]. For any particular transcription factor, the sequence-function relationship for regions outside of the DNA binding domain is often unclear, making it difficult to predict how evolutionary changes in this region will impact transcription factor function without empirical tests [26].…”

Section: Introductionmentioning

confidence: 99%

Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability inDrosophila melanogaster

Ertl,

Bayala,

Siddiq

et al. 2024

Preprint

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Pioneer factors are critical for gene regulation and development because they bind chromatin and make DNA more accessible for binding by other transcription factors. The pioneer factor Grainy head (Grh) is present across metazoans and has been shown to retain a role in epithelium development in fruit flies, nematodes, and mice despite extensive divergence in both amino acid sequence and length. Here, we investigate the evolution of Grh function by comparing the effects of the fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) Grh orthologs on chromatin accessibility, gene expression, embryonic development, and viability in transgenic D. melanogaster. We found that the Caenorhabditis elegans ortholog rescued cuticle development but not full embryonic viability in Drosophila melanogaster grh null mutants. At the molecular level, the C. elegans ortholog only partially rescued chromatin accessibility and gene expression. Divergence in the disordered N-terminus of the Grh protein contributes to these differences in embryonic viability and molecular phenotypes. These data show how pioneer factors can diverge in sequence and function at the molecular level while retaining conserved developmental functions at the organismal level.

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The molecular grammar of protein disorder guiding genome-binding locations

Cited by 16 publications

References 89 publications

Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability inDrosophila melanogaster

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