Grant: Project Grant

In the intricate world of our DNA, a group of special proteins known as histones ensure that our genes are read accurately - like playing the right tune in a song. These histones are essential, guiding when and where genes activate, whether it's for a baby or an adult, a skin cell or a brain cell. A recent breakthrough unveiled 63 mutations in histones among patients facing severe neurological challenges. These individuals struggle to achieve basic milestones such as walking and speaking. Some also grapple with aggressive behaviors and seizures that disrupt their daily lives. These mutations are rare yet immensely significant, given histones' pivotal role in life. Our team has made headway in revealing how a specific change in one part of a histone's structure triggers neuroinflammation and subsequent neurodegeneration. We're now on a quest to decipher why a different mutation in the same part of the histone tail causes an entirely distinct disease, impacting other tissues and leading to issues like morbid obesity, kidney and liver problems, and musculoskeletal dysfunctions. We're also investigating two nearby mutations that result in separate brain disorders - one marked by cognitive difficulties and aggressive behavior, and the other by microcephaly and severe neurodegeneration. Our findings indicate that many of these histone mutations alter how DNA can be accessed. Proper histone function relies on modifications, but in these mutated histones, this process goes awry. Using cutting-edge molecular and biochemical analyses, growing tiny brain-like structures called "3D organoids," and using engineered mouse models, we will uncover how these mutations contribute to brain dysfunction and disease, and pinpoint affected genes that could respond to therapy. Our discoveries will serve as a foundation for new treatments, not only for children grappling with severe brain conditions but also for those battling life-threatening cancers driven by histone mutations.