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The cell’s biomolecular complexes are often coupled to each other in time and space, giving rise to new forms of function and regulation. Using single-molecule fluorescence- and force-based methods, Liu investigates the coordination and competition among principal machineries involved in gene expression. The goal is to elucidate how cellular processes collectively respond to changing conditions during growth, development, and disease.

Virtually all aspects of the cellular life involve the operation of nanometer-scale machines, commonly known as molecular motors, which convert chemical energy into mechanical work. The advent of single-molecule techniques has made it possible to examine these tiny machines in unprecedented detail by following each individual movement, pull, and twist in real time. It is thus not surprising that, over the past decade, a soaring number of molecular motors have been subjected to single-molecule interrogation, uncovering a wealth of novel information and, oftentimes, unexpected phenomena.

However, much less attention has been paid to how these machines interact or cooperate—and these questions represent a crucial next step toward connecting insights from in vitro experiments back to the cellular environment. Liu’s research takes this step, using state-of-the-art single-molecule tools, sometimes in combination with genomic approaches, to understand how motor-driven processes are integrated into a coherent network in the cell, and how their interplay evolves in response to environmental changes.

Through his training, Liu has established expertise in two primary classes of single-molecule methods: fluorescence-based detection and force-based manipulation. As a graduate student at Harvard University, he used single-molecule fluorescence spectroscopy to examine the movement of HIV reverse transcriptase, the target of many anti-AIDS therapies, as it makes a DNA copy of viral RNA. During his postdoc, Liu utilized high-resolution optical tweezers to investigate the bacteriophage phi29 DNA packaging motor, which is a ring-shaped ATPase, a common type of molecular motor. His research revealed the precisely coordinated chemical and mechanical transitions that its five ring subunits must undergo, as well as an unexpected division of labor among these subunits—insights that may apply to many molecular motors with similar structures.

Liu’s current research focuses on the fundamental gene expression process, during which a series of molecular machines act in concert to convert genetic DNA code into RNA messages, and subsequently into protein products. Among the specific interests of his laboratory is the interplay between bacterial transcription, translation, and the RNA degradation machineries that controls the fate of RNA transcripts and the output of protein synthesis.

Another area of focus for the lab lies within more complex eukaryotic cells. Liu is designing experiments to investigate how RNA polymerase reads through eukaryotic chromatin, a process regulated by transcription factors, the remodeling of chromatin, and epigenetic modifications. In addition, he is interested in chromatin replication, a process in which the replisome not only faithfully duplicates the genetic code but also helps transmit epigenetic information from parental to daughter strands. The lab is seeking to visualize the hierarchy of molecular events involved in this process, and the fates of its players.