Sheng received a Ph.D. in Biostatistics from Harvard University. He worked at Stanford University as a visiting scholar and at University of Illinois at Urbana-Champaign as an assistant and an associate professor before moving to UC San Diego. His group studies gene regulation by developing both experimental and computational technologies. His lab discovered transposon-mediated re-wiring of transcription networks that govern mammalian embryonic development, and contributed to initiating "comparative epigenomics" - using cross-species epigenomic comparison to annotate the genomes.