Poster Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

ZMYND8: A novel transcriptional regulator of the dorsal-ventral patterning of the brain (#29)

Juli Wang 1 , Nicole Green 1 , Hannah Danon 1 , Kerith-Rae Dias 1 , Gavin Sutton 2 , Tony Roscioli 3 , Anai Gonzalez Cordero 4 , Irina Voineagu 1
  1. School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia
  2. The University of Sydney, Randwick, NSW, Australia
  3. 2. Neuroscience Research Australia, UNSW, Sydney, NSW, Australia
  4. Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia

The Zinc Finger Myeloid, Nervy, and DEAF-1 (MYND) type containing 8 (ZMYND8) is a master epigenetic regulator. Mutations in ZMYND8 are linked to a syndromic form of intellectual disability. We harnessed the power of single-cell RNA sequencing (scRNA-seq) and multi-omic analyses to investigate the role of ZMYND8 in brain organoids that are differentiated from wildtype and ZMYND8-deficient (KO) iPSCs. We observed that ZMYND8 KO led to a striking change in the cellular compositions and transcriptomic profiles of brain organoids, suggesting a dorsal-to-ventral identity shift of the brain organoids. RNA splicing analysis of mutant organoids suggests ZMYND8 is required for the correct splicing frequency of genes involved in neural development, synaptic biology, and cilia biology. Furthermore, at the pathway levels, we uncovered that ZMYND8 regulates SHH and WNT-signalling pathways, explaining the shift in mutant organoids from a dorsal towards a ventral fate. Overall, these data indicate that ZMYND8 is critical for brain development and plays a key role in orchestrating the gene and RNA splicing networks required for brain development.