Elucidating epigenetic mechanisms of disease and treatment in Weaver and Sotos syndromes

/Abstract Growth and neurodevelopment are fundamental to child health and have an epigenetic basis that remains poorly understood, posing a barrier to therapeutic development. Mendelian disorders of the epigenetic machin- ery (MDEMs) are monogenic syndromes characterized molecularly by altered epigenomes and phenotypically by disrupted growth and neurodevelopment. They can thus inform the epigenetic basis of growth and neurode- velopment. Weaver and Sotos syndromes are MDEMs caused by disruption of distinct histone writers that ex- hibit highly similar phenotypes of pathological overgrowth and intellectual disability (ID). The current proposal uses these disorders to elucidate epigenetic mechanisms of overgrowth and ID and to test a targeted treat- ment. The central hypothesis is that genetic disruption of the Weaver histone writer causes overgrowth and ID by altering cell type-specific chromatin and transcriptional pathways responsible for normal growth and neuro- development, which converge with disrupted Sotos pathways, and both are ultimately correctable by pharma- cological manipulation of a shared histone mark. Our rationale is that elucidating chromatin and gene expres- sion changes that cause skeletal overgrowth and ID in two rare diseases will inform our understanding of these central regulators of epigenetic marks and especially how they regulate normal growth and neurodevelopment and may reveal a common drug target. The central hypothesis will be tested by pursuing three specific aims: 1. Establish the neurological phenotype and causal mechanisms in our Weaver mouse model; 2. Elucidate epige- netic mechanisms of skeletal overgrowth and evaluate treatment in Weaver mice; and 3. Determine human disease mechanisms and therapeutic responses in Weaver iPSC models and compare to Sotos. In aim 1, data establishing skeletal overgrowth due to excess osteogenesis in a Weaver syndrome mouse model are present- ed. Studies to elucidate the neurobehavioral phenotype and its basis are proposed. In aim 2, preliminary data show an epigenetic drug (GSKJ4) reverses excess osteogenesis and the altered transcriptome in vitro in Wea- ver mouse osteoblasts. Preclinical trials with GSKJ4 in Weaver mice alongside transcriptomic and epigenomic profiling are proposed. In aim3, data from human Sotos cells show altered transcription of pathways shared with Weaver. Cross-disorder comparison of epigenetic mechanisms, phenotypes, and drug responses in pa- tient iPSC-based models are proposed. This research is innovative because it uses a cross-species, state-of- the-art multi-omics approach on models from two related disorders and tests an epigenetic drug’s ability to re- verse skeletal overgrowth and neurobehavioral phenotypes. The proposed research is significant because it establishes both human organoid and mouse disease models for testing targeted, mechanism-based therapies for currently untreatable phenotypes. Moreover, this work advances knowledge of fundamental epigenetic mechanisms controlling growth and neurodevelopment and has the potential to uncover new epigenetic para- digms, including treatments for MDEMs and more common lifelong neurological and growth disorders. Project Number: 1R01HD115624-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jill Fahrner | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $674,312 | Activity Code: R01 | Study Section: Therapeutic Approaches to Genetic Diseases Study Section[TAG] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11562401A1