Enhancer Features that Drive Formation of Transcriptional Condensates

Krishna Shrinivas; Benjamin R Sabari; Eliot L Coffey; Isaac A Klein; Ann Boija; Alicia V Zamudio; Jurian Schuijers; Nancy M Hannett; Phillip A Sharp; Richard A Young; Arup K Chakraborty

doi:10.1016/j.molcel.2019.07.009

Enhancer Features that Drive Formation of Transcriptional Condensates

Mol Cell. 2019 Aug 8;75(3):549-561.e7. doi: 10.1016/j.molcel.2019.07.009.

Authors

Affiliations

¹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA.
³ Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁵ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
⁶ Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].

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.

Keywords: coactivator; condensate; cooperativity; enhancer; multivalence; phase separation; regulatory element; specificity; transcription; transcription factor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence / genetics
Binding Sites / genetics
Chromatin / genetics*
DNA / genetics
DNA-Binding Proteins / genetics
Enhancer Elements, Genetic*
Gene Expression Regulation
Genomics
Mice
Mouse Embryonic Stem Cells
Transcription Factors / genetics*
Transcription, Genetic*

Substances

Chromatin
DNA-Binding Proteins
Transcription Factors
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding