ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program.

Area of Science:

• Neuroscience
• Genetics
• Chromatin Biology

Background:

• ZMYND11 mutations cause ZMYND11-related syndromic intellectual disability (ZRSID), characterized by developmental delays and seizures.
• Neuronal ZMYND11 loss in mice leads to abnormal gene expression, reduced neuronal connectivity, and behavioral deficits.

Purpose of the Study:

• To investigate the mechanism by which ZMYND11 regulates gene expression in the brain.
• To explore the therapeutic potential of targeting KMT2A for ZRSID.

Main Methods:

• Utilized a ZMYND11 knockout mouse model to study ZRSID.
• Investigated ZMYND11's interaction with histone methyltransferase KMT2A (MLL1).
• Employed a degron-tagged ZMYND11 mouse model and KMT2A inhibitor revumenib in primary cortical neurons.

Main Results:

• ZMYND11 deletion in neurons upregulates non-neuronal gene programs, causing impaired dendritic branching and motor abnormalities.
• ZMYND11 directly inhibits KMT2A, a key player in oncogenic and developmental gene programs.
• A ZRSID-associated mutation disrupts ZMYND11-KMT2A interaction, highlighting its importance in brain development.
• KMT2A inhibition with revumenib attenuated gene expression changes caused by ZMYND11 loss.

Conclusions:

• ZMYND11 acts as a crucial regulator of neuronal gene expression by inhibiting KMT2A.
• The ZMYND11-KMT2A interaction is vital for normal brain development.
• Targeting KMT2A activity presents a potential therapeutic strategy for ZRSID.