The regulation of Ler and its transcript, ler, is complex and many-fold. The plasmid encoded regulator (per) directly activates the region of the LEE1 operon which encodes Ler. Integration host factor is also a direct activator of ler and binds upstream of its promoter.
Jeannette Barba and her colleagues at the National Autonomous University of Mexico elucidated a positive regulatory loop between Ler, ler, GrlA, and grlRA. GrlA is also a LEE encoded regulator of the LEE pathogenicity island. They found that GrlA activates ler, and that Ler activates grlRA indicating a loop of activation wherein a protein product activates a transcript whose protein product activates the transcript of the original protein. Ler activates grlRA only if H-NS is present, this is not the case for GrlA activation of ler.
Quorum sensing plays a role in Ler regulation. LuxS is an important protein involved in quorum sensing, particularly in the synthesis of autoinducer molecules. Quorum-sensing E. coli regulator A (QseA) is found in LuxS systems and activates transcription of ler. Fis, a nucleoid associated protein essential for EPEC's ability to form attaching and effacing lesions, partly acts through activation of Ler expression. BipA, a ribosomal binding GTPase and prolific regulator of EPEC virulence, transcriptionally regulates Ler from an upstream position where it also regulates other genes.
The Ler protein also represses its own transcript on the LEE1 operon through DNA looping which prevents RNA polymerase from completing transcription.