TitleUnique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage.
Publication TypeJournal Article
Year of Publication2020
AuthorsChu, Chi-Shuen, Hellmuth Johannes C., Singh Rajat, Ying Hsia-Yuan, Skrabanek Lucy, Teater Matthew R., Doane Ashley S., Elemento Olivier, Melnick Ari M., and Roeder Robert G.
JournalMol Cell
Volume80
Issue5
Pagination845-861.e10
Date Published2020 12 03
ISSN1097-4164
KeywordsAnimals, B-Lymphocytes, Cell Line, Tumor, Germinal Center, HEK293 Cells, Humans, Locus Control Region, MEF2 Transcription Factors, Mice, Mice, Knockout, Organic Cation Transporter 2, Proto-Oncogene Mas, Proto-Oncogene Proteins c-bcl-6, Trans-Activators
Abstract

<p>Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type-defining LCR.</p>

DOI10.1016/j.molcel.2020.10.036
Alternate JournalMol Cell
PubMed ID33232656
PubMed Central IDPMC7737631
Grant ListR01 CA178765 / CA / NCI NIH HHS / United States
R01 AI148387 / AI / NIAID NIH HHS / United States
R01 CA228528 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA163086 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
P01 CA229086 / CA / NCI NIH HHS / United States