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Nucleated transcriptional condensates amplify gene expression

Nature Cell Biology volume 22, pages 1187–1196 (2020)Cite this article

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Abstract

Membraneless organelles or condensates form through liquid–liquid phase separation1,2,3,4, which is thought to underlie gene transcription through condensation of the large-scale nucleolus5,6,7 or in smaller assemblies known as transcriptional condensates8,9,10,11. Transcriptional condensates have been hypothesized to phase separate at particular genomic loci and locally promote the biomolecular interactions underlying gene expression. However, there have been few quantitative biophysical tests of this model in living cells, and phase separation has not yet been directly linked with dynamic transcriptional outputs12,13. Here, we apply an optogenetic approach to show that FET-family transcriptional regulators exhibit a strong tendency to phase separate within living cells, a process that can drive localized RNA transcription. We find that TAF15 has a unique charge distribution among the FET family members that enhances its interactions with the C-terminal domain of RNA polymerase II. Nascent C-terminal domain clusters at primed genomic loci lower the energetic barrier for nucleation of TAF15 condensates, which in turn further recruit RNA polymerase II to drive transcriptional output. These results suggest that positive feedback between interacting transcriptional components drives localized phase separation to amplify gene expression.

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Fig. 1: Sequence-dependent biomolecular interactions drive intracellular phase behaviour.
Fig. 2: Transcriptional condensates colocalize with and recruit additional CTD.
Fig. 3: Pol II CTD clusters influence nucleation of transcriptional condensates.
Fig. 4: OptoTAF15 selectively enriches transcription-related proteins.
Fig. 5: Condensation of transcriptional IDRs enhances transcription.

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Data availability

All data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

Code availability

Custom code used to process and analyse the images, as detailed in the Methods, are available upon request.

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Acknowledgements

We thank M. Levine and M. Haataja, as well as J. Eeftens and other members of the Brangwynne laboratory for helpful discussions and comments on this manuscript. This work was supported by the Howard Hughes Medical Institute, and grants from the National Institutes of Health 4D Nucleome Program (U01 DA040601), the Princeton Center for Complex Materials, a National Science Foundation supported MRSEC (DMR 1420541), as well an NSF CAREER award (1253035).

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Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA

    Ming-Tzo Wei, Yi-Che Chang, Shunsuke F. Shimobayashi, Yongdae Shin, Amy R. Strom & Clifford P. Brangwynne

  2. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Yi-Che Chang

  3. Department of Mechanical Engineering, Seoul National University, Seoul, Korea

    Yongdae Shin

  4. Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Korea

    Yongdae Shin

  5. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Clifford P. Brangwynne

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Contributions

M.-T.W. and C.P.B. designed research; M.-T.W., Y.-C.C. and Y.S. created constructs and performed experiments; M.-T.W., Y.-C.C, S.F.S. and A.R.S. analysed data; M.-T.W. and C.P.B. wrote the paper; and all authors reviewed and edited the paper.

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Correspondence to Clifford P. Brangwynne.

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Extended data

Extended Data Fig. 1 The amino acid sequence of intrinsically disordered regions.

Polar residues are shown in green; positively charged are shown in blue; negatively charged are shown in red; hydrophobic are shown in black; aromatic residues are shown in orange.

Extended Data Fig. 2 Statistical tests of the preferential condensation in nucleoplasm or cytoplasm.

a, OptoIDRs concentration outside clusters from individual cells under blue-light-illumination. Solid and open symbols represent C*Cyto and C*Nuc, respectively. The lines indicate the mean and error bars are s.d.s derived from the number of cells (as indicated in the panel) collected from 3 independent experiments. b, The ratio of C*Cyto and C*Nuc along with statistical tests to demonstrate that optoTAF15 has a preferred phase separate in the nucleus as compared to the cytoplasm. Dash line represents that C*Cyto equals to C*Nuc. In the optoTAF15 charged mutation constructs, the ratio C*Cyto over C*Nuc decreases as charged amino acids in optoTAF15 are mutated. Furthermore, the ratio maintains the same level for aromatic group mutation. These data suggest that charge-mediated interactions would contribute to TAF15’s preferential condensation in the nucleoplasm compared within cytoplasm. Data are plotted as calculated ratio of mean ± s.d. derived from the number of cells (as indicated in the panel a). c, Phase behaviors show strong dependence on protein sequence for phenylalanine mutation (Phenylalanine, F to Alanine, A). Steady-state cytoplasmic optoIDR concentration outside clusters (CCyto) from individual cells under blue light illumination as a function of optoIDR initial concentration (C0_Cyto). Solid and open symbols represent individual cells with or without light-activated assemblies respectively; solid line has slope of 1 and y-intercept of 0. d, The molecular interactions, β, along with statistical tests to demonstrate that optoTAF15 has a significantly stronger attractive forces to drive phase separate in the nucleus as compared to the cytoplasm, while optoFUS and optoEWS have little to no significant difference between cytoplasm and nucleus. Data are plotted as calculated ratio of mean ± s.d. derived from 20 of cells. P values are determined statistical significance obtained in pairwise two-sided Fisher’s exact tests in (a, b, and d). Statistical source data are provided in Source Data Extended Data Fig. 2.

Source data

Extended Data Fig. 3 Determinant of molecular interactions and inhabitation of transcription kinesis.

a, The molecular interactions, β, of the different constructs. Data are plotted as mean ± s.d. (n = 20 cells collected from 3 independent experiments). b, To assume the interactions are additive, the IDR interaction would be defined by subtracting the contribution of the construct of mCherry tagged Cry2 (βmch::Cry2) from the interaction strength (β) for optoFUS. To compare the contribution from FUSIDR and Cry2, the molecular interactions were systematically analyzed from the different constructs. The data showed that, the attractive forces from FUSIDR are around three-fold higher than the forces from Cry2 in the absence of blue light illumination. c, Fluorescent images of ATP depleted-cells expressing optoIDRs and eGFP-CTD after blue-light illumination. Cells were treated for 30 min in 2 mM sodium azide and 10 mM deoxyglucose to deplete ATP and inhibit phosphorylation. Cell nucleus is outlined by dotted line. Arrowheads point to optoIDR condensates colocalized with recruit CTD. Scale bar same for all images. d, CTD partition coefficients in various optoIDR condensates. These data suggest that each member of the FET family is capable of recruiting unphosphorylated CTD, while an unrelated protein cannot and indicates that EWS is indeed able to recruit CTD. The lines indicate the mean and error bars are s.d.s derived from the number of cells (as indicated in the panel) collected from 3 independent experiments. P values are determined statistical significance obtained in pairwise two-sided Fisher’s exact tests. e, THZ1 treatment to decrease the nucleoplasmic saturation concentration of optoTAF15. Nucleoplasmic saturation concentration as function of time over 3 hours. Black and red points represent untreated and THZ1-treated-cells, respectively. Data are plotted as mean ± s.d. (n = 15 cells collected from 3 independent experiments). Statistical source data are provided in Source Data Extended Data Fig. 3.

Source data

Extended Data Fig. 4 Repeated assemble and disassemble of optoIDRs condensates.

a, OptoDDX4 and TRF1-CTD cells, b, Actinomycin D (Act D) and α-amanitin treated optoTAF15 cells, and c, optoTAF15 and TRF1-CTD cells were exposed to blue light activation condition for 1 min to assemble clusters and then incubated in the absence of blue light for 9 min to disassemble clusters. Cell images before and after activation at the end of each cycle are shown. Experiment was repeated independently 3 times with similar results. d, Colocalization for TRF1-CTD various optoIDRs. Colocalization correlation obtained from Pearson’s Correlation results of nuclear pixel intensity (nucleoli excluded) for cells as shown in (a) and (c). Pearson Correlation Coefficient in each frames of successive cycles of activation shows higher colocalization function in optoTAF15 than optoDDX4. Additionally, colocalization correlation of optoIDRs as a function the lag cycle also shows higher colocalization function in optoTAF15 than optoDDX4. Those date indicate that optoTAF15 condensates specifically seed at these tethered loci, TRF1-CTD, and maintain repetitive localization in 8 successive cycles of activation, while optoDDX4 condensates, a control protein, do not seed at TRF1-CTD loci. e, OptoTAF15 and TRF1-CTD cells were exposed to continuous blue light illumination. OptoTAF15 condensates remain stable at telomere tethered CTD sites Experiment was repeated independently 3 times with similar result. Scale bar,, 5μm. Statistical source data are provided in Source Data Extended Data Fig. 4.

Source data

Extended Data Fig. 5 Immunofluorescence images of endogenous proteins and image of cell with nascent RNA and with telomeric repeat-containing RNA.

a, In the absence of blue light illumination, optoTAF15 cells were fixed using 4% paraformaldehyde. Then, the Immunofluorescence images were observed under super-resolution Airyscan microscopy. Cell nucleus is outlined by dotted line. Experiment was repeated independently 3 times with similar result. The scale bar is the same for all images. b, In cells expressing optoTAF15 and TRF1-CTD and kept in dark, the EU signal was distributed evenly throughout the nucleoplasm. Image of cell with nascent RNA production labeled by EU incorporation. In cells expressing optoTAF15 and TRF1-CTD under blue light illumination, nascent RNA transcripts were present in optoTAF15 condensates. White arrows indicate light-illuminated TAF15 condensates colocalize TRF1-CTD clusters and enhance local transcription RNA EU clusters. Experiment was repeated independently 3 times with similar result. c, Colocalization for TRF1-CTD with nascent RNA optoTAF15. Degree of colocalization is measured by Pearson’s correlation coefficient of nuclear pixel intensity (nucleoli excluded) between nascent RNA EU versus TRF1-CTD and optoTAF15 versus TRF1-CTD channels; +1 indicates perfect correlation, 0 no correlation, and -1 perfect anti-correlation. Colocalization results indicate that light-illuminated optoTAF15 condensates strongly colocalize with local nascent RNA EU production at TRF1-CTD clusters. Experiment was repeated independently 3 times with similar result. d, White arrows indicate light-illuminated optoTAF15 condensates colocalize TRF1-CTD clusters and enhance local transcription TERRA labeled by RNA fluorescence in situ hybridization at telomeres. e, Colocalization results indicate that light-illuminated optoTAF15 condensates enhance colocalization with transcription TERRA at TRF1-CTD clusters. Experiment was repeated independently 3 times with similar result. Statistical source data are provided in Source Data Extended Data Fig. 5.

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Wei, MT., Chang, YC., Shimobayashi, S.F. et al. Nucleated transcriptional condensates amplify gene expression. Nat Cell Biol 22, 1187–1196 (2020). https://doi.org/10.1038/s41556-020-00578-6

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