2. Academic Validation
  3. lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation

lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation

  • Nat Cell Biol. 2020 Oct;22(10):1211-1222. doi: 10.1038/s41556-020-0572-2.
Kaveh Daneshvar 1 2,  M Behfar Ardehali 3 4,  Isaac A Klein 5 6,  Fu-Kai Hsieh 3 4,  Arcadia J Kratkiewicz 1 2,  Amin Mahpour 1 2,  Sabrina O L Cancelliere 2 7,  Chan Zhou 1 2,  Brett M Cook 8,  Wenyang Li 1 2,  Joshua V Pondick 1 2,  Sweta K Gupta 1 2,  Sean P Moran 1 2,  Richard A Young 5 9,  Robert E Kingston 3 4,  Alan C Mullen 10 11 12
Affiliations

Affiliations

  • 1 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
  • 2 Harvard Medical School, Boston, MA, USA.
  • 3 Department of Molecular Biology and MGH Research Institute, Massachusetts General Hospital, Boston, MA, USA.
  • 4 Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 7 Harvard Stem Cell Institute, Cambridge, MA, USA.
  • 8 Optical Biosystems, Inc, Santa Clara, CA, USA.
  • 9 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 10 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA. [email protected].
  • 11 Harvard Medical School, Boston, MA, USA. [email protected].
  • 12 Harvard Stem Cell Institute, Cambridge, MA, USA. [email protected].
PMID: 32895492 DOI: 10.1038/s41556-020-0572-2
Abstract

Cooperation between DNA, RNA and protein regulates gene expression and controls differentiation through interactions that connect regions of nucleic acids and protein domains and through the assembly of biomolecular condensates. Here, we report that endoderm differentiation is regulated by the interaction between the long non-coding RNA (lncRNA) DIGIT and the bromodomain and extraterminal domain protein BRD3. BRD3 forms phase-separated condensates of which the formation is promoted by DIGIT, occupies enhancers of endoderm transcription factors and is required for endoderm differentiation. BRD3 binds to histone H3 acetylated at lysine 18 (H3K18ac) in vitro and co-occupies the genome with H3K18ac. DIGIT is also enriched in regions of H3K18ac, and the depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings show that cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest that protein-lncRNA phase-separated condensates have a broader role as regulators of transcription.

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