How polymer-loop-extruding motors shape chromosomes
Chromosomes are extremely long, active polymers that are spatially organized across multiple scales to promote cellular functions, such as gene transcription and genetic inheritance. During each cell cycle, chromosomes are dramatically compacted as cells divide and dynamically reorganized into less compact, spatiotemporally patterned structures after cell division. These activities are facilitated by DNA/chromatin-binding protein motors called SMC complexes. Each of these motors can perform a unique activity known as “loop extrusion,” in which the motor binds the DNA/chromatin polymer, reels in the polymer fiber, and extrudes it as a loop. Using simulations and theory, I show how loop-extruding motors can collectively compact and spatially organize chromosomes in different scenarios. First, I show that loop-extruding complexes can generate sufficient compaction for cell division, provided that loop-extrusion satisfies stringent physical requirements. Second, while loop-extrusion alone does not uniquely spatially pattern the genome, interactions between SMC complexes and protein “boundary elements” can generate patterns that emerge in the genome after cell division. Intriguingly, these “boundary elements” are not necessarily stationary, which can generate a variety of patterns in the neighborhood of transcriptionally active genes. These predictions, along with supporting experiments, show how SMC complexes and other molecular machinery, such as RNA polymerase, can spatially organize the genome. More generally, this work demonstrates both the versatility of the loop extrusion mechanism for chromosome functional organization and how seemingly subtle microscopic effects can emerge in the spatiotemporal structure of nonequilibrium polymers.
Finding Needles in Genomic Haystacks
The ability to read the DNA sequences of different organisms has transformed biology in much the same way that the telescope transformed astronomy. And yet, much of the sequence found in these genomes is as enigmatic as the Rosetta Stone was to early Egyptologists. With the aim of making steps to crack the genomic Rosetta Stone, I will describe unexpected ways of using the physics of information transfer first developed at Bell Labs for thinking about telephone communications to try to decipher the meaning of the regulatory features of genomes. Specifically, I will show how we have been able to explore genes for which we know nothing about how they are regulated by using a combination of mutagenesis, deep sequencing and the physics of information, with the result that we now have falsifiable hypotheses about how those genes work. With those results in hand, I will show how simple tools from statistical physics can be used to predict the level of expression of different genes, followed by a description of precision measurements used to test those predictions. Bringing the two threads of the talk together, I will think about next steps in reading and writing genomes at will.