Cell reports · 2026
The MLLT3 YEATS domain binds histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking transcription and RNA signaling to regulate hematopoiesis.
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Boulton Adam, Kabra Ashish, Achille Nicholas, Adelman Emmalee R, Anastasakis Dimitrios G, Beckedorff Felipe, Reddy Cingaram Pradeep Kumar, Roller Devin G, Zhang Ying, Leach Benjamin, Gioeli Daniel, Shiekhattar Ramin, Yokoyama Akihiko, Hafner Markus, Figueroa Maria, Zeleznik-Le Nancy, Bushweller John H
Аннотация
MLLT3 (AF9) is a critical regulator of hematopoiesis. The YEATS domain of MLLT3 binds to acylated histones (H3K9ac/cr). We showed that the YEATS domain also binds to RNA. PAR-CLIP data demonstrated binding to the snRNA 7SK. Biochemical studies show high-affinity binding to stem loop 4 (SL4) of 7SK. NMR chemical shift perturbation mapping of the binding site for 7SK SL4 on the YEATS domain was used to generate a model of the complex. Based on the model, mutations were identified that disrupt 7SK binding without affecting H3K9ac binding. Introduction of these mutations into full-length MLLT3 skewed hematopoiesis toward the lymphoid lineage, abrogated the transforming properties of NES-AF9, and reduced the self-association of MLLT3. PRO-Seq and RNA-Seq identified genes driving the observed phenotype and showed a block in transcriptional initiation with the loss of RNA binding. Our results demonstrate a critical role for RNA binding in the function of MLLT3.