Mapping and prediction of quantitative transcription factor dosage effects to understand variation in craniofacial morphology and disease

点击翻译按钮获取中文摘要

PROJECT SUMMARY Accumulating evidence suggests robustness of transcriptional regulation, yet human genetic studies indicate phenotypic sensitivity to transcription factor (TF) dosage in both complex traits and rare disorders, motivating quantitative studies of TF dosage effects. These features are exemplified by the development of the human face, which is frequently disrupted in a range of syndromes with typical features. The aim of this proposal is to develop and apply tools to precisely modulate dosage of craniofacial TFs in cranial neural crest cells, the progenitors of the face, and assess effects across multiple biological levels – molecular, cellular, and morphological. The proposal initially focuses on SOX9, using diverse approaches to understand the rules that determine which regulatory elements and genes are sensitive to SOX9 dosage (Aim 1), as well as their phenotypic consequences (Aim 2). Then, such rules will be generalized to five additional craniofacial TFs (Aim 3) and used to dissect mechanisms underlying genetic variants associated with craniofacial morphology or disease (Aim 4). These studies will reveal drivers of craniofacial morphological and disease variation, provide general insights into transcriptional regulation, and help transform our approach to studying TF function, from binary to quantitative in nature. The proposed research, along with a comprehensive plan for my career development, combines my scientific background and postdoctoral training in functional genomics, gene regulation, and human genetics with opportunities for additional training in machine learning, mouse genetics, and morphological analysis. I will be mentored by Drs. Joanna Wysocka and Jonathan Pritchard in a vibrant scientific environment (Stanford Chemical and Systems Biology) and receive additional training from my advisory committee of Drs. James Ferrell, Anshul Kundaje, and Benedikt Hallgrimsson. My transition to independence will be facilitated by participation in both scientific and non-scientific trainings and workshops, as well as experience in presenting my work at scientific conferences. I will also gain experience mentoring students and technicians, and will hone my grant management and writing skills. Collectively, my mentors have guided over 25 of their former postdocs to independent academic research positions, and they will provide practical advice and feedback during my faculty job search. My long-term career goal is to direct an independent research program aimed at understanding the molecular underpinnings of quantitative variation in craniofacial morphology and disease risk. So far I have achieved significant progress towards this goal through my research experience, publications, and engagement with the broader scientific community. I firmly believe, however, that a K99 mentored phase will maximize my chances for success by providing access to key resources and training that would be otherwise lacking from my postdoctoral experience.