The chromatin reader ZMYND8 recruits the NuRD component GATAD2A through its MYND domain to regulate MAPT213 long...

The zinc finger MYND-type containing eight protein (ZMYND8) is a chromatin reader that regulates neuronal gene expression by controlling the microtubule-associated protein tau (MAPT) locus. Here, we investigate how ZMYND8 regulates expression of the long non-coding RNA MAPT213 through its interaction with GATA zinc finger domain containing 2A (GATAD2A), a component of the Nucleosome Remodelling and Deacetylase complex. ZMYND8 exhibits opposite regulatory effects on protein-coding MAPT and non-coding MAPT213 transcripts in a manner dependent on its MYND domain, promoting MAPT expression while suppressing MAPT213 levels. Chromatin immunoprecipitation experiments demonstrated that ZMYND8 specifically recruits GATAD2A to the MAPT213 internal regulatory region, establishing a direct link between protein binding and transcriptional control. We determined the crystal structure of the ZMYND8 coiled-coil MYND domain at high resolution, revealing a homodimeric architecture. The MYND domain specifically recognizes GATAD2A through direct interaction with proline-rich motifs in GATAD2A's central region. Structure-function analysis identified critical binding interface residues, while quantitative measurements revealed moderate-affinity interactions enhanced through multivalent binding mechanisms. These findings establish the molecular basis for ZMYND8-mediated recruitment of chromatin remodeling complexes to specific genomic loci and provide a structural framework for understanding transcriptional regulation of MAPT213.