BRAT1 associates with INTS11/INTS9 heterodimer to regulate key neurodevelopmental genes.

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• The Integrator complex regulates gene expression, with subunits implicated in neurodevelopmental disorders.
• BRAT1 is associated with neurodegenerative and neurodevelopmental conditions.

Approach:

• Investigated the interaction between Integrator subunits INTS9/INTS11 and BRAT1 in human cell lines (HEK293T, NT2).
• Assessed the impact of BRAT1 depletion on neural differentiation and gene expression.
• Examined the co-occupancy of BRAT1 and INTS11 at target gene promoters.

Key Points:

• BRAT1 interacts with Integrator subunits INTS9 and INTS11, forming a trimeric complex.
• BRAT1 depletion severely disrupts neural differentiation and neuronal gene activation.
• BRAT1 facilitates the recruitment of INTS11 to the promoters of neuronal genes regulated by REST.
• Disease-associated BRAT1 mutations weaken its interaction with the INTS11/INTS9 heterodimer.

Conclusions:

• The BRAT1/INTS11/INTS9 complex is essential for activating key neuronal genes during human neural differentiation.
• Defects in this complex due to BRAT1 mutations contribute to neurodevelopmental disorder phenotypes.