Weinian Shou

Indiana University School of Medicine, USA

SET  and  MYND  domain–containing  proteins  (SMYDs)  are  lysine methyltransferases  that   regulate   gene   expression   by   modifying histone H3. Among them, SMYD1 is known for its role in cardiomyocyte differentiation,  while  growing  evidence  links  SMYD4  to  congenital heart  defects  (CHDs).  In  zebrafish,  smyd4  is  maternally  expressed, abundant  during  early  embryogenesis,  and   later  enriched  in  the developing  cardiovascular  system.  Loss  of  smyd4   causes  severe defects:   about   70%   of   maternal/zygotic   mutants   arrest  during

gastrulation, and the rest develop cardiac malformations, indicating essential functions in both early patterning and cardiogenesis. To investigate SMYD4 mechanisms, we generated a human embryonic  stem   cell  (hESC)  cardiac  differentiation  model.  CRISPR/Cas9-mediated  SMYD4 knockout impaired mesendoderm and cardioprogenitor formation, mirroring zebrafish defects. Single-cell  transcriptomic,  ATAC-seq,   CUT&RUN,   and   proteomic   profiling   revealed  broad disruptions in chromatin accessibility and transcriptional regulation. These findings establish SMYD4 as a conserved epigenetic regulator required for early lineage specification and heart development, offering mechanistic insight into its association with CHDs.