Research Interests. single molecule biophysics, super-resolution imaging, cell division, gene regulation
Research Description. My laboratory focuses on developing novel single-molecule imaging tools in live cells to probe various dynamic aspects of cellular processes. We develop single-molecule gene expression reporting systems and chromosomal DNA conformation markers to probe the dynamics of gene regulation and transcription in live bacterial cells. We also pioneered the use of superresolution imaging to probe the structure, function and dynamics of the bacterial cell division machinery. Our work is at the frontier of imaging dynamic cellular processes, and has enabled new quantitative understandings of gene regulation and cell division. Recently we are expanding our horizons by collaborating with experts of different fields to map the spatial organization of a single cell’s genome and epigenetic markers, and to develop new single-molecule based technologies for sensitive early detection of cancer markers in blood samples.
Our major research topics are:
- Noise control mechanism in stochastic gene expression
Gene expression is inherently stochastic. How cells battle noise in gene expression in order to achieve robust growth and development has been the subject of intense studies in the past decade. Majority of the studies focused on the intrinsic noise of gene expression, which are fluctuations caused by the intrinsic properties of biochemical reactions in gene expression at the low-copy number regime. To find out how cells repress intrinsic noise using autoregulatory transcription factors, we developed a single-molecule gene expression reporter to monitor the stochastic expression of a transcription factor and its autoregulatory actions. We discovered that intrinsic noise has negligible effect on the overall gene expression noise. Instead, extrinsic noise, or fluctuations caused by different compositions of cellular factors in different cells, dominates noise in gene expression. Consequently, cells use negative autoregulation to counteract extrinsic noise in order to achieve a homogenous gene expression level. These findings significantly advance our understanding of the operational principle of gene regulatory networks, and signal a major change in the field of stochastic gene expression. New studies are now focusing on the influence and origin of extrinsic noise, as now we understand the final gene expression level distribution is dominated by extrinsic noise, and cells develop specific mechanisms to counteract such fluctuations in gene expression.
- Hensel Z., Feng H., Han B., Hatem C., Wang J*., Xiao J.*, Stochastic expression dynamics of transcription factor revealed by single-molecule noise analysis, 2012, Nat. Struct. Mol. Biol. 19(8):797-802, *cocorresponding authors. (selected for cover image), [PMID:22751020]
- Feng H., Hensel Z., Xiao J.*, Wang J.*, Analytical calculation of protein production distributions in models of clustered protein expression, Phys Rev Lett E, 2012, 85(3), 031904 *cocorresponding authors, [PMID:22587120]
- Structure, function and dynamics of bacterial cell division complex
In bacteria, cell division is carried out by a highly conserved supramolecular complex, the divisome. Understanding the structure and function of the divisome is important for developing new antibiotics. Central to the divisome is a ring-like structure formed by the essential FtsZ protein, named the Z-ring. The Z-ring recruits all other divisome components, and possibly generates a mechanic force to constrict the inner membrane. However, it has been difficult to probe the in vivo structural organization of the Z-ring because of its small size and highly dynamic nature. We made our first major contribution to the field by illustrating the structural organization of the Z-ring in live E. coli cells using single-molecule based superresolution imaging. The structure provides an important foundation to understand how different components of the divisome are assembled and coordinated to carry out cell division. Next, we showed that there exists a multi-layered protein network residing in the cytoplasm, physically connecting the Z-ring to the chromosome to stabilize the Z-ring and coordinate cell division with chromosome segregation. Most importantly, we provide substantial evidence to demonstrate that, in contrary to the common belief, the Z-ring is not the major constrictive force generator. Instead, septum closure rate is limited by cell wall growth, and further modulated by nucleoid segregation. Our work redefines the role of the Z-ring in bacterial cell division, and promotes a new, holistic view of the divisome.
- Coltharp C., Buss J., Plumer T., Shtengel G., Hess H., Xiao J., Defining the rate-limiting processes in bacterial cytokinesis, PNAS, 2016, Feb 23, 113(8):E1044-53
- Buss J, Coltharp C., Shtengel G, Yang X, Hess H and Xiao J., A multi-layered protein network maintains the stability of the FtsZ-ring and modulate constriction dynamics in E.coli, PLoS Genetics, 2015, Apr 7;11(4):e1005128, [PMID: 2584771]
- Buss J., Coltharp C., Huang T., Pohlmeyer C., Hatem C., Xiao J., In vivo organization of the FtsZ-ring by ZapA and ZapB revealed by quantitative super-resolution microscopy, 2013, Mol. Microbio. Jul 17. 89(6), 1099-1120 (selected for cover image), [PMC3894617]
- Fu G., Huang T., Buss J., Coltharp C., Hensel Z., Xiao J., In vivo structure of the E. coli FtsZ-ring revealed by photoactivated Localization Microscopy (PALM), 2010, PLoS One, 5, e12680, [PMC2938336]
- Spatial organization of transcription
Recently we are venturing into a new direction, the spatial organization of transcription. Recent studies suggest that genes are spatially organized; where they are and how they are organized are important for their transcription activities. To test this hypothesis, we are developing new imaging techniques to visualize chromosomal DNA conformation and transcription activity in individual cells. The first set of DNA localization markers we developed allowed us to probe the dynamics of transcription factor-mediated DNA looping in live E. coli cells, and relate to transcription activity of the gene it controls. We are currently developing new superresolution methods to probe both genome organization and transcription activity in the same cells. We expect this line of work to provide new insight into the spatial regulation of transcription.
- Hensel Z.,Weng X., Lagda A., Xiao J., Transcription factor mediated DNA looping probed by high-resolution, single-molecule imaging in live E. coli cells, 2013, PLoS Biology, 11(6):e1001591, [PMID:23853547]
- Weng X., Xiao J., Spatial organization of transcription in E. coli, 2014, Trends in Genetics, 2014 Jul;30(7):287-297, [PMID: 24862529]
- Coltharp C, Yang X., Xiao J., Quantitative analysis of single-molecule superresolution images, 2014, Curr Opin Struct Biol, Aug 29;28C:112-121, [PMC4252250]
A complete list of publications, excluding chapters and articles not accessed by PubMed, can be found at: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/43454614/?sort=date&direction=descending