# Deciphering the roles of COMPASS-related methyltransferases in intellectual and developmental disability > **NIH NIH F32** · BAYLOR COLLEGE OF MEDICINE · 2022 · $64,924 ## Abstract Project Summary Roughly 1,000 genes have been associated with intellectual and developmental disability (IDD), but targeted treatment options are lacking. Despite this genetic heterogeneity, many implicated genes have similar functions, suggesting they converge on shared mechanisms. There is a critical need to identify potential convergent mechanisms to develop therapeutics for each subclass of genes associated with IDD. This proposal focuses on six related chromatin regulators to determine whether IDD-causing mutations in these genes affect similar molecular pathways. These six SET methyltransferases (SETD1A, SETD1B, KMT2A, KMT2B, KMT2C, and KMT2D) each form a separate COMPASS complex that methylates H3K4. Haploinsufficiency of each gene causes a separate neurodevelopmental syndrome with intellectual disability as a feature. My central hypothesis is that mutations in these COMPASS-related methyltransferases cause intellectual and developmental disability through dysregulating a shared set of genes due to changes in H3K4 methylation patterns. The alternative hypothesis is that IDD results from broad gene expression dysregulation of non-overlapping gene sets. The proposed aims will test both hypotheses and the data I will generate will provide new insight into mechanisms driving IDD irrespective of the outcome. I will use a robust CRISPR interference-based platform in human induced pluripotent stem cells (iPSCs) to knockdown and study these six COMPASS-related genes. In Aim 1, I will elucidate dysregulated molecular pathways due to haploinsufficiency of COMPASS methyltransferases via transcriptomic and epigenomic profiling. These data will allow me to test the hypothesis that loss of these genes leads to dysregulation of similar gene sets and determine whether these similarities can be explained by shared genomic binding sites. In Aim 2, I will functionally characterize morphological and neurophysiological effects of COMPASS methyltransferase haploinsufficiency on human iPSC-derived neurons. These experiments will reveal either common or divergent signatures at the cellular and network levels and will provide insight into the pathophysiology of intellectual disability. This proposal is significant because it will establish a framework to elucidate convergent mechanisms in IDD that could be scaled to a broader set of genes in future studies. My fellowship proposal also outlines a rigorous training plan focused on five specific areas to support my long-term career goal of becoming an independent investigator: (1) identifying interesting research questions and designing rigorous experiments; (2) effective scientific communication in oral presentations, manuscript writing, and grant writing; (3) novel research techniques, including CRISPR methods, stem cell culture, calcium imaging, and chromatin profiling; (4) mentoring students and collaborating with colleagues; and (5) preparation for an independent career. Through direct supervision from Dr. Huda... ## Key facts - **NIH application ID:** 10505308 - **Project number:** 1F32NS127854-01 - **Recipient organization:** BAYLOR COLLEGE OF MEDICINE - **Principal Investigator:** Ryan Dhindsa - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $64,924 - **Award type:** 1 - **Project period:** 2022-09-01 → 2023-07-03 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10505308 ## Citation > US National Institutes of Health, RePORTER application 10505308, Deciphering the roles of COMPASS-related methyltransferases in intellectual and developmental disability (1F32NS127854-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10505308. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*