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Papers by Mark Kittisopikul

Proceedings of the National Academy of Sciences, 2010

Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of ... more Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of interactions (architecture) and susceptibility to stochastic fluctuations (noise). Whether the link between circuit architecture and noise is of biological importance remains, however, poorly understood. To investigate this problem, we performed a computational study of gene expression noise for all possible circuit architectures of feed-forward loop (FFL) motifs. Results revealed that FFL architectures fall into two categories depending on whether their ON (stimulated) or OFF (unstimulated) steady states exhibit noise. To explore the biological importance of this difference in noise behavior, we analyzed 858 documented FFLs in Escherichia coli that were divided into 39 functional categories. The majority of FFLs were found to regulate two subsets of functional categories. Interestingly, these two functional categories associated with FFLs of opposite noise behaviors. This opposite noise preference revealed two noise-based strategies to cope with environmental constraints where cellular responses are either initiated or terminated stochastically to allow probabilistic sampling of alternative states. FFLs may thus be selected for their architecture-dependent noise behavior, revealing a biological role for noise that is encoded in gene circuit architectures.

Proceedings of the National Academy of Sciences, 2012

From microbial biofilm communities to multicellular organisms, 3D macroscopic structures develop ... more From microbial biofilm communities to multicellular organisms, 3D macroscopic structures develop through poorly understood interplay between cellular processes and mechanical forces. Investigating wrinkled biofilms of Bacillus subtilis, we discovered a pattern of localized cell death that spatially focuses mechanical forces, and thereby initiates wrinkle formation. Deletion of genes implicated in biofilm development, together with mathematical modeling, revealed that ECM production underlies the localization of cell death. Simultaneously with cell death, we quantitatively measured mechanical stiffness and movement in WT and mutant biofilms. Results suggest that localized cell death provides an outlet for lateral compressive forces, thereby promoting vertical mechanical buckling, which subsequently leads to wrinkle formation. Guided by these findings, we were able to generate artificial wrinkle patterns within biofilms. Formation of 3D structures facilitated by cell death may underlie self-organization in other developmental systems, and could enable engineering of macroscopic structures from cell populations.

Cell, 2012

Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive bioch... more Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive biochemical interaction networks. Despite their complexity, bacterial pathogens have evolved parsimonious mechanisms to hijack these systems. Here, we develop a tractable experimental and theoretical model to uncover fundamental operating principles both in mammalian cell polarity and bacterial pathogenesis. Using synthetic derivatives of the enteropathogenic E. coli guaninenucleotide exchange factor (GEF) Map, we discover that Cdc42 GTPase signal transduction is controlled by the interaction between Map and F-actin. Mathematical modeling reveals how actin dynamics coupled to a Map-dependent positive feedback loop spontaneously polarizes Cdc42 on the plasma membrane. By rewiring the pathogenic signaling circuit to operate through β-integrin stimulation, we further show how Cdc42 is polarized in response to an extracellular spatial cue. Thus, a molecular pathway of polarity is proposed, centered on the interaction between GEFs and F-actin, which is likely to function in diverse biological systems.

APS Bulletin of the American Physical Society. APS March Meeting 2011 Volume 56, Number 1. Monday... more APS Bulletin of the American Physical Society. APS March Meeting 2011 Volume 56, Number 1. Monday–Friday, March 21–25, 2011; Dallas, Texas. ...

Molecular biology of the cell, Jan 26, 2015

The nuclear lamina is a key structural element of the metazoan nucleus. However, the structural o... more The nuclear lamina is a key structural element of the metazoan nucleus. However, the structural organization of the major proteins composing the lamina remains poorly defined. Using three-dimensional Structured Illumination Microscopy and computational image analysis, we have characterized the supramolecular structures of lamin A, C, B1 and B2 in mouse embryo fibroblast nuclei. Each isoform forms a distinct fiber meshwork, having comparable physical characteristics with respect to mesh edge length, mesh face area and shape, and edge connectivity to form faces. Some differences were found in face areas between isoforms due to variation in the edge lengths and number of edges per face, suggesting that each meshwork has somewhat unique assembly characteristics. In fibroblasts null for the expression of either lamins A/C or lamin B1, the remaining lamin meshworks are altered compared with the lamin meshworks in wild type nuclei or nuclei lacking lamin B2. Nuclei lacking LA/C exhibit sli...

Proceedings of the National Academy of Sciences, 2010

Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of ... more Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of interactions (architecture) and susceptibility to stochastic fluctuations (noise). Whether the link between circuit architecture and noise is of biological importance remains, however, poorly understood. To investigate this problem, we performed a computational study of gene expression noise for all possible circuit architectures of feed-forward loop (FFL) motifs. Results revealed that FFL architectures fall into two categories depending on whether their ON (stimulated) or OFF (unstimulated) steady states exhibit noise. To explore the biological importance of this difference in noise behavior, we analyzed 858 documented FFLs in Escherichia coli that were divided into 39 functional categories. The majority of FFLs were found to regulate two subsets of functional categories. Interestingly, these two functional categories associated with FFLs of opposite noise behaviors. This opposite noise preference revealed two noise-based strategies to cope with environmental constraints where cellular responses are either initiated or terminated stochastically to allow probabilistic sampling of alternative states. FFLs may thus be selected for their architecture-dependent noise behavior, revealing a biological role for noise that is encoded in gene circuit architectures.

Proceedings of the National Academy of Sciences, 2012

From microbial biofilm communities to multicellular organisms, 3D macroscopic structures develop ... more From microbial biofilm communities to multicellular organisms, 3D macroscopic structures develop through poorly understood interplay between cellular processes and mechanical forces. Investigating wrinkled biofilms of Bacillus subtilis, we discovered a pattern of localized cell death that spatially focuses mechanical forces, and thereby initiates wrinkle formation. Deletion of genes implicated in biofilm development, together with mathematical modeling, revealed that ECM production underlies the localization of cell death. Simultaneously with cell death, we quantitatively measured mechanical stiffness and movement in WT and mutant biofilms. Results suggest that localized cell death provides an outlet for lateral compressive forces, thereby promoting vertical mechanical buckling, which subsequently leads to wrinkle formation. Guided by these findings, we were able to generate artificial wrinkle patterns within biofilms. Formation of 3D structures facilitated by cell death may underlie self-organization in other developmental systems, and could enable engineering of macroscopic structures from cell populations.

Cell, 2012

Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive bioch... more Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive biochemical interaction networks. Despite their complexity, bacterial pathogens have evolved parsimonious mechanisms to hijack these systems. Here, we develop a tractable experimental and theoretical model to uncover fundamental operating principles both in mammalian cell polarity and bacterial pathogenesis. Using synthetic derivatives of the enteropathogenic E. coli guaninenucleotide exchange factor (GEF) Map, we discover that Cdc42 GTPase signal transduction is controlled by the interaction between Map and F-actin. Mathematical modeling reveals how actin dynamics coupled to a Map-dependent positive feedback loop spontaneously polarizes Cdc42 on the plasma membrane. By rewiring the pathogenic signaling circuit to operate through β-integrin stimulation, we further show how Cdc42 is polarized in response to an extracellular spatial cue. Thus, a molecular pathway of polarity is proposed, centered on the interaction between GEFs and F-actin, which is likely to function in diverse biological systems.

APS Bulletin of the American Physical Society. APS March Meeting 2011 Volume 56, Number 1. Monday... more APS Bulletin of the American Physical Society. APS March Meeting 2011 Volume 56, Number 1. Monday–Friday, March 21–25, 2011; Dallas, Texas. ...

Molecular biology of the cell, Jan 26, 2015

The nuclear lamina is a key structural element of the metazoan nucleus. However, the structural o... more The nuclear lamina is a key structural element of the metazoan nucleus. However, the structural organization of the major proteins composing the lamina remains poorly defined. Using three-dimensional Structured Illumination Microscopy and computational image analysis, we have characterized the supramolecular structures of lamin A, C, B1 and B2 in mouse embryo fibroblast nuclei. Each isoform forms a distinct fiber meshwork, having comparable physical characteristics with respect to mesh edge length, mesh face area and shape, and edge connectivity to form faces. Some differences were found in face areas between isoforms due to variation in the edge lengths and number of edges per face, suggesting that each meshwork has somewhat unique assembly characteristics. In fibroblasts null for the expression of either lamins A/C or lamin B1, the remaining lamin meshworks are altered compared with the lamin meshworks in wild type nuclei or nuclei lacking lamin B2. Nuclei lacking LA/C exhibit sli...