[Chiba Medical Society Young Investigator Award Minireview] Catalytic and non-catalytic functions of histone methyltransferase SETD1A in diseases

[ABSTRACT]Histone modification plays an indispensable role in the regulation of transcription. The SET1/MLL family proteins are histone methyltransferases that are conserved from yeast to humans. SETD1A is one of six human SET1/MLL family proteins that primarily catalyzes H3K4 tri-methylation in vitro. SETD1A interacts with multiple subunits to form a complex, the generation of which enhances enzymatic activity and contributes to SETD1A-specific functions. As H3K4 tri-methylation serves as an active transcription marker, the SETD1A complex is believed to promote the transcription of downstream targets. Over the past decade, considerable work has been conducted on the involvement of SETD1A in human diseases. SETD1A is upregulated in cancers and its elevated expression is correlated with poor prognosis, whereas loss-of-function mutations in SETD1A are associated with neurodevelopmental disorders, such as schizophrenia. A SETD1A knockout mouse model has been characterized by abnormal neurotransmission and neural circuit formation and exhibits schizophrenia-like symptoms. Consequently, SETD1A is assumed to play essential roles in cell proliferation, differentiation, and metabolism. Recently, our group and others have identified the non-catalytic functions of SETD1A, as well as the non-canonical substrates of SETD1A. Importantly, many studies have revealed that SETD1A regulates the DNA damage repair pathway via both canonical and non-canonical routes. However, the underlying molecular mechanisms remain unclear and require further investigation. Here, we review the catalytic and non-catalytic functions of SETD1A in different diseases.