Many non-Mendelian (polygenic) human genetic diseases involve multiple causal loci in noncoding regions of the genome, implicating mutations in regulatory elements rather than protein-coding genes as the cause of these diseases. Deciphering the etiology of these human genetic diseases requires an understanding of how genes are regulated during development and homeostasis to produce functional cell states. This regulation is encoded both through epigenetic chromatin state, and genetically encoded in the DNA sequence of regulatory elements such as enhancers, promoters, silencers, and insulators. However, these regulatory elements and their activity states in human cells are not resolvable with current technologies. As aberrant gene regulation likely underlies many human diseases, understanding (1) the function of regulatory DNA elements and (2) their activity dynamics during healthy human development are essential. To address these two problems, I propose to: (i) develop new experimental methods to profile multimodal chromatin state in single cells; (ii) identify alterations in regulatory element activation states that guide cell fate choice during human hematopoiesis; (iii) identify the DNA sequence features important for regulatory element function; (iv) build community tools and resources for the analysis of single-cell chromatin data. Together these aims will provide methods and resources for the interrogation of the human functional genome, and the identification of regulatory state dynamics that generate human cell types. To succeed in achieving these aims, I will pursue additional training supported by co-mentors Dr. Rahul Satija (single-cell biology), Dr. Vijay Sankaran (hematopoiesis), Dr. Danny Reinberg (gene regulation), and Dr. David Knowles (machine learning). I have developed a 5-year career development plan that integrates scientific training in hematopoiesis and gene regulation, practical training and mentorship in deep learning, extensive leadership training through courses and mentorship, and seminars and workshops on academic writing. My team of scientific mentors will provide further guidance and mentorship in academic job searches. The New York Genome Center is an ideal environment for research and further career development, providing the cutting-edge research facilities and opportunities for further career development in a rich interdisciplinary environment. Completion of the proposed research program and career development plan will launch my independent scientific career as a leader in the field of single-cell epigenomics.
Information in the human genome encodes a multitude of functional cell states. How this information is decoded to produce these states, and how aberrant encodings produce aberrant states, is not well known. This project aims to develop a suite of experimental and computational methods to identify the changes in regulatory states that occur during hematopoiesis and predict how changes to the genome sequence may impact healthy human development.
