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The faithful inheritance and precise expression of genetic information is carried out by specialized macromolecular machines. These nanometer-scale entities need to navigate through complex cellular environments in order to access, modify, and decode the genome and epigenome of an organism. Using single-molecule fluorescence- and force-based methods, Liu investigates the coordinated behavior of machineries that act on bacterial and eukaryotic chromosomes.

Virtually all aspects of cellular life are driven by nanometer-scale biomolecular machines, which generate forces in the piconewton range and operate at energies just above those of the thermal bath. The advent of single-molecule techniques has made it possible for scientists to follow how these tiny devices move, pull, and twist one molecule at a time, thereby discerning previously hidden dynamics and, oftentimes, unexpected phenomena. The Liu laboratory leverages state-of-the-art single-molecule fluorescence detection and force manipulation tools, sometimes in combination with novel genomic approaches, to investigate how random molecular behaviors lead to non-random biochemical outcomes and directional information flow in the cell.

Currently, the lab’s efforts focus on understanding the biophysical principles underlying the interaction, cooperation, and competition between molecular machines that act on chromatin—genome-organizing complexes made up of DNA and histone proteins. Using multicolor fluorescence imaging, they studied the invasion of transcription factors into a wrapped nucleosome, the basic structural unit of eukaryotic chromosomes. They have found that the cooperative ability of transcription factors (such as Sox2 and Oct4) to bind chromatin depends on the positions and orientations of their binding motifs within a nucleosome. Using microscopic tweezers formed by focused laser beams, they have demonstrated that chromatin-modifying enzymes such as the Polycomb repressive complex are able to bridge non-adjacent nucleosomes. This activity likely contributes to the transcriptional silencing of compacted chromatin domains. Other recent work revealed that the ring-shaped eukaryotic DNA unwinding enzyme known as CMG harbors a gate that allows it to transition between single-stranded and duplex DNA. This finding challenges the prevailing dogma regarding how DNA replication machinery operates and has major implications for DNA replication and repair.

In a separate line of research, Liu’s group is studying the coordination of molecular machines that control the life cycle of cellular RNA. They recently developed an RNA sequencing method named SEnd-seq, to simultaneously map both ends of a transcript with nucleotide resolution. They used this method to profile the transcriptome of the bacterium Escherichia coli and discovered a large number of overlapping, bidirectional transcription termination sites located between pairs of convergent genes. This discovery suggests a new potential mechanism for termination driven by RNA polymerase collisions. They are now applying SEnd-seq to other bacterial species, including Mycobacterium tuberculosis.

Together, these studies highlight that the mechanical characteristics of chromatin and chromatin-processing machines constitute an important dimension for gene regulation. In the future, the lab will seek to elucidate how DNA replication and transcription machineries motor along and negotiate with hierarchically organized chromosomes. These inquiries will shed light on the mechanisms by which genetic and epigenetic stability is maintained across generations