Technological advancement is the driving force in modern biology. The Xia lab develops high-throughput & interdisciplinary technologies to tackle challenges in biological sciences. We keep our radars switched on to all interesting biological, chemical, computational, and physical discoveries, and learn from them to develop new technologies. Meanwhile, we are building an interdisciplinary and collaborative team, embracing creative minds and expertise across fields.

For decades, forward and reverse genetic screens have been central in functional studies of genes and beyond. Forward genetic screen starts with phenotypes and aims to determine the genetic basis responsible for a given phenotype, while reverse genetic screen starts from known genes - or more broadly, DNA sequences - and assays the effect of each gene upon perturbation. However, traditional genetic screen typically requires a large-scale experimental setup, and is strongly limited by the available resource and experimental feasibility.

The Xia lab proposed and developed in silico genetic screen (ISGS) research framework as the next-generation approach to genetic discoveries. The ISGS framework integrates advanced machine learning models and high-throughput in silico genetic perturbation. Similar to the experimental genetic screen, the ISGS framework interrogates the effect of genetic perturbation through accurate computational modeling in an ultra-high-throughput scenario. We recently developed C.Origami, a deep neural network that performs de novo prediction of cell type-specific chromatin organization with optimal performance. Coupling the C.Origami model with the ISGS framework, we systematically analyzed how individual DNA elements affect chromatin organization across the genome. We continue developing novel high-throughput in silico genetic screen frameworks that will enable more widespread applications to drive our discovery in the genome sciences.

Chemical modifications modulate various biological processes. DNA methylation (5mC) and TET-protein-mediated DNA methylation-derivatives (5hmC, 5fC and 5caC) represent one major part of epigenetics. The critical information to understand the function of an epigenetic factor is to profile its genome-wide distribution pattern. We have developed several unique and robust chemical methods to analyze the genome distribution map of 5fC and 5hmC. Represented by 'fC-CET' and 'CLEVER-seq', these methods demonstrated the concept of 'bisulfite-free & base-resolution' analysis of DNA epigenetic modifications. We used these methods to analyze the epigenomes in embryonic stem cells and even in single cells of the early developing embryo. These technologies will help us understand the molecular basis of epigenetic gene expression regulation and how these chemical modifications – and their modifier and reader proteins – affect mammalian development.