Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

In this study, we characterize the fusion protein produced by the ZMYND11-MBTD1 translocation in acute myeloid leukemia. We express the fusion protein and necessary controls in K562 Cells. The fusion protein assembles ZMYND11 factor with the full acetyltransferase NuA4/TIP60 complex. The fusion protein leads to mislocalization NuA4/TIP60 complex in gene bodies, thereby increasing H4ac in specific gene targets. Finally, chromatin aberration is linked to aberrant gene expression and spliced isoforms. Overall design: Flag-ChIP sequencing of MBTD1, full length ZMYND11, truncated ZMYND11 [aa1-409], and ZMYND11-MBTD1 fusion-3xFlag-2xstrep in K562 cells, and Oxford Nanopore Technologies long-read RNA sequencing of ZMYND11 KO K562 cells expressing either MBTD13xFlag-2xstrep, truncated ZMYND11 3xFlag-2xstrep or ZMYND11-MBTD1 fusion 3xFlag-2xstrep in K562 cells. K562 cells expressing endogenous ZMYND11 and MBTD1 3xFlag-2xstrep are used as control.