PT  - JOURNAL ARTICLE
AU  - Kaveh Daneshvar
AU  - M. Behfar Ardehali
AU  - Isaac A. Klein
AU  - Arcadia J. Kratkiewicz
AU  - Chan Zhou
AU  - Amin Mahpour
AU  - Brett M. Cook
AU  - Wenyang Li
AU  - Joshua V. Pondick
AU  - Sean P. Moran
AU  - Richard A. Young
AU  - Robert E. Kingston
AU  - Alan C. Mullen
TI  - lncRNA <em>DIGIT</em> and BRD3 protein form phase-separated condensates to regulate endoderm differentiation
AID  - 10.1101/547513
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 547513
4099  - http://biorxiv.org/content/early/2019/02/12/547513.short
4100  - http://biorxiv.org/content/early/2019/02/12/547513.full
AB  - Gene programs that control differentiation are regulated through the interplay between DNA, RNA, and protein. Cooperation among these fundamental cellular components can occur through highly structured interactions connecting domains formed by specific sequences of nucleotides, ribonucleotides, and/or amino acids and also through the assembly of biomolecular condensates. Here, we show that endoderm differentiation is regulated through the interaction of the long noncoding (lnc) RNA DIGIT and the bromodomain and extra-terminal (BET) domain family protein BRD3. BRD3 forms phase-separated condensates that contain DIGIT, occupies enhancers of endoderm transcription factors, and is required for endoderm differentiation. Purified BRD3 binds to acetylated histone H3 lysine 18 (H3K18ac) in vitro and occupies regions of the genome enriched in H3K18ac during endoderm differentiation, including the key transcription factors that regulate endoderm differentiation. DIGIT is also enriched in regions of H3K18ac, and depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings support a model where cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest a broader role for protein-lncRNA phase-separated condensates as regulators of transcription in development.