Oral Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

Complete definition of cis-acting mutations at the fimS locus regulating type 1 pili in E. coli by saturating genome editing (#26)

Swaine L. Chen 1 , Huibin Zhang 2 , Teodorus Theo Susanto 3 , Yue Wan 3
  1. National University of Singapore and Genome Institute of Singapore, Singapore, SINGAPORE
  2. Infectious Diseases, Genome Institute of Singapore, Singapore
  3. Genome Institute of Singapore, Singapore
Type 1 pili are the dominant virulence factor for E. coli to cause urinary tract infection, an infection affecting billions of women. The regulation of type 1 pilus expression is notable for an epigenetic invertible element, denoted fimS, controlling phase variation and transcription of the fim operon encoding type 1 pili. fim expression, in turn, is important for virulence during UTI. Previous studies have identified several DNA binding proteins which converge at fimS; these include the tyrosine recombinases FimB and FimE as well as IHF and LRP. Prior studies of cis-acting mutations in fimS have been limited to relatively low-throughput methods or methods which require alteration of copy number or chromosomal context. Leveraging a recently developed negative selection system as well as single molecule sequencing, we have now performed a high throughput saturating mutagenesis of the chromosomal fimS locus in its native context, enabling the first complete map of cis-acting mutations affecting phase variation at fimS. This map captures several known sequences important for phase variation, including the fimS inverted repeats and the -10 and -35 regions of the fimS promoter. This map also identifies a novel inverted repeat just outside the fimS region which affects phase regulation by specifically altering transcript levels of one of the fim genes. We now provide a comprehensive view of the functional sites within fimS, elucidating a previously unknown regulatory element, and this genomic editing technique may be useful for studying the mechanisms underlying other phase variable loci in pathogenic and nonpathogenic organisms.