Abstract
Enhancers are DNA elements that are bound by transcription factors (TFs), which recruit coactivators and the transcriptional machinery to genes. Phase-separated condensates of TFs and coactivators have been implicated in assembling the transcription machinery at particular enhancers, yet the role of DNA sequence in this process has not been explored. We show that DNA sequences encoding TF binding site number, density, and affinity above sharply defined thresholds drive condensation of TFs and coactivators. A combination of specific structured (TF-DNA) and weak multivalent (TF-coactivator) interactions allows for condensates to form at particular genomic loci determined by the DNA sequence and the complement of expressed TFs. DNA features found to drive condensation promote enhancer activity and transcription in cells. Our study provides a framework to understand how the genome can scaffold transcriptional condensates at specific loci and how the universal phenomenon of phase separation might regulate this process. Shrinivas et al. demonstrate that specific types of motif compositions encoded in DNA drive localized formation of transcriptional condensates. These findings explain how phase separation can occur at specific genomic locations and shed light on why only some genomic loci become highly active enhancers.
| Original language | English |
|---|---|
| Pages (from-to) | 549-561.e7 |
| Journal | Molecular Cell |
| Volume | 75 |
| Issue number | 3 |
| DOIs | |
| State | Published - 8 Aug 2019 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2019 Elsevier Inc.
Funding
We acknowledge members of Chakraborty and Young labs for helpful discussions. We acknowledge the support of Wendy Salmon and the W.M. Keck Microscopy Facility at the Whitehead Institute. This work was supported by grants from the NSF ( PHY-1743900 ; A.K.C., R.A.Y., and P.A.S.), by the NIH ( GM123511 [R.A.Y.] and P01-CA042063 [P.A.S.]), and in part by a Koch Institute Support (core) grant ( P30-CA14051 ) from the National Cancer Institute (P.A.S). Additional support was provided by Damon Runyon Cancer Research Foundation Fellowship ( 2309-17 ; B.R.S.), NSF Graduate Research Fellowship (A.V.Z.), NWO Rubicon Fellowship (J.S.), Swedish Research Council Postdoctoral Fellowship ( VR 2017-00372 ; A.B.), and an NIH training grant ( T32CA009172 ; I.A.K.). We acknowledge members of Chakraborty and Young labs for helpful discussions. We acknowledge the support of Wendy Salmon and the W.M. Keck Microscopy Facility at the Whitehead Institute. This work was supported by grants from the NSF (PHY-1743900; A.K.C. R.A.Y. and P.A.S.), by the NIH (GM123511 [R.A.Y.] and P01-CA042063 [P.A.S.]), and in part by a Koch Institute Support (core) grant (P30-CA14051) from the National Cancer Institute (P.A.S). Additional support was provided by Damon Runyon Cancer Research Foundation Fellowship (2309-17; B.R.S.), NSF Graduate Research Fellowship (A.V.Z.), NWO Rubicon Fellowship (J.S.), Swedish Research Council Postdoctoral Fellowship (VR 2017-00372; A.B.), and an NIH training grant (T32CA009172; I.A.K.). Conceptualization, K.S. B.R.S. P.A.S. A.K.C. and R.A.Y.; Methodology, K.S. B.R.S. A.K.C. A.V.Z. J.S. E.L.C. I.A.K. and A.B.; Software, K.S.; Formal Analysis, K.S.; Investigation, K.S. B.R.S. A.V.Z. J.S. E.L.C. I.A.K. and A.B.; Resources, J.S. I.A.K. A.B. N.M.H. P.A.S. A.K.C. and R.A.Y.; Data Curation, K.S.; Writing – Original Draft, K.S. B.R.S. P.A.S. A.K.C. and R.A.Y.; Writing – Review & Editing, all authors; Visualization, K.S. B.R.S. and A.V.Z.; Supervision, P.A.S. A.K.C. and R.A.Y.; Funding Acquisition, P.A.S. A.K.C. and R.A.Y. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics. I.A.K. is a consultant to InfiniteMD, Best Doctors, and Foundation Medicine and is a shareholder of InfiniteMD. P.A.S. is a member of the board and shareholder in Syros and a member of the scientific advisory board of Dewpoint. A.K.C. is a member of the Scientific Advisory Boards of Dewpoint Therapeutics and Omega Therapeutics. All other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| Camp4 Therapeutics | |
| Dewpoint Therapeutics | |
| Omega Therapeutics | |
| National Science Foundation | PHY-1743900 |
| National Institutes of Health | P30-CA14051, P01-CA042063 |
| National Cancer Institute | T32CA009172 |
| National Institute of General Medical Sciences | R01GM123511 |
| Damon Runyon Cancer Research Foundation | 2309-17 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Vetenskapsrådet | VR 2017-00372 |
Keywords
- coactivator
- condensate
- cooperativity
- enhancer
- multivalence
- phase separation
- regulatory element
- specificity
- transcription
- transcription factor