ACT-SIGNAL · Lysine Acetylation: The Scope and Function in Gene Activation

Transcription, the first and most crucial step in decoding the genome, is orchestrated by an extensive repertoire of transcription factors (TFs). These TFs transmit diverse signals to the nucleus, directing precise temporal and spatial gene activation programs. They employ a diverse array of transcription coactivators to impact transcription, including lysine acetyltransferases (KATs), an evolutionarily conserved group of coactivators found in all eukaryotes. Lysine acetylation serves as a hallmark of active promoters and enhancers, with the level of acetylation correlating with gene expression. Despite a strong correlation between acetylation and gene activation, the causal role of acetylation in transcription activation remains debated. Our recent research has revealed that inhibiting the catalytic activity of CBP/p300 acetyltransferase halts the transcription of numerous genes without impacting DNA accessibility or TF binding. A fundamental question that remains unanswered is whether acetylation is directly involved in gene activation, what the nature of acetylation sites involved is, and what are the underlying mechanisms by which acetylation regulates transcription activation. In ACT-SIGNAL, we will take an integrated approach, combining CRISPR-based gene editing, quantitative proteomics, and genomics to investigate the function of lysine acetyltransferases in proteome-scale acetylation and explore the mechanisms by which acetylation promotes gene activation. Ultimately, ACT-SIGNAL aims to establish an integrated model for acetylation-dependent dynamic gene regulation. This endeavor has the potential to provide a major conceptual advance in our understanding of how transcription factors and acetyltransferases collaborate to promote transcription activation – the crucial first step in genetic information decoding.