Federal Project Grant Summary

Yale University received a $248,823 Project Grant award from the National Human Genome Research Institute (NHGRI) under the Human Genome Research program (CFDA 93.172), effective May 1, 2026 through April 30, 2029. This award supports the development of integrative machine learning models to elucidate the functional consequences of nuclear DNA organization on gene regulation across human tissues and mammalian species. The research deliverables include novel, open-source, and interpretable computational tools that predict Hi-C (High-Throughput Chromosome Conformation Capture) contacts from nucleotide sequences across 80 human tissues, establish rules of chromatin organization shared across 100 mammalian species through translation between Hi-C and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) data, and quantify the impact of variations in nuclear organization on tissue-specific transcriptional and post-transcriptional regulation using machine learning and long-read RNA sequencing.

The project addresses a critical gap in understanding how genome organization influences gene regulation and contributes to health and disease outcomes. By integrating multiple next-generation sequencing assays—Hi-C, ATAC-seq, and RNA-seq—the award funds the creation of computational models that identify sequence determinants of three-dimensional chromatin structure and translate these structural principles across mammalian evolution. The research is structured across three aims, with initial phases focused on model development and validation followed by application to human tissue-specific regulatory mechanisms, ultimately providing the scientific community with validated tools for discovering regulatory mechanisms underlying nuclear DNA organization variation.