Q Yin(1), S Hachim(1), T Boettger(1), T Braun(1)

1. Group Boettger, Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany

The INO80 chromatin remodeler complex regulates transcription and chromosome maintenance through interactions with transcription factors and non-coding RNAs. It comprises eight conserved core subunits and six metazoan-specific subunits, including TFPT, which has been identified as a fusion partner of transcription factor 3 in childhood leukemia and is predicted to have both DNA and kinase binding activities.

This study investigates the molecular basis and cell-of-origin of fetal lethality caused by TFPT deletion. We found that TFPT⁻/⁻ embryos exhibit lethality beginning at E11.5, with prominent cardiovascular defects, notably ventricular septal defects. Using Cre-recombinase lines targeting specific cardiac cell types, we identified cardiac progenitor and smooth muscle cells as likely origins of the phenotype.

Transcriptomic analysis revealed downregulation of synaptic function genes and upregulation of cell cycle genes in TFPT⁻/⁻ embryos, indicating disrupted neuronal development and cell cycle regulation. These findings were supported by reduced cardiac innervation and evidence of cell cycle arrest. Co-immunoprecipitation confirmed TFPT’s interaction with INO80, as well as additional unique partners that appear to function independently of the complex. ChIP-seq analysis showed that TFPT’s DNA-binding activity primarily depends on the canonical INO80 complex. Notably, GO enrichment analysis of TFPT-specific interactors identified a strong association with mRNA splicing. Combined with ChIP-seq evidence of INO80-dependent DNA binding function, these findings suggest a potential INO80-independent role of TFPT in regulating mRNA splicing, however, the specific gene targets and their relevance to the observed phenotypes require further explorations.