Programmed heterogeneity: epigenetic mechanisms in bacteria

Abstract

Contrary to the traditional view that bacterial populations are clonal, single-cell analysis reveals that phenotypic heterogeneity is common in bacteria. Formation of distinct bacterial lineages appears to be frequent during adaptation to harsh environments, including the colonization of animals by bacterial pathogens. Formation of bacterial subpopulations is often controlled by epigenetic mechanisms that generate inheritable phenotypic diversity without altering the DNA sequence. Such mechanisms are diverse, ranging from relatively simple feedback loops to complex self-perpetuating DNA methylation patterns.

Keywords: Bacterial Genetics; DNA Methylation; DNA Methylation Pattern; DNA Methyltransferase; Epigenetics; Escherichia coli; Gene Regulation; Genetic Switch; Phase Variation; Reversible Bistability.

FIGURE 1.

Left panel, Waddington's artistic drawing of an “epigenetic landscape” as a ball that falls to stable valleys from unstable ridges (adapted from Ref. 1). Right panel, bistability viewed as the fall of a ball from an unstable state on a ridge to a stable state in a valley. In phase variation, the valley state is metastable, and the ball periodically returns to the ridge.

FIGURE 2.

A, competence development in B. subtilis, an example of bistability created by a positive feedback loop. B, the lysis/lysogeny decision in bacteriophage λ, an example of bistability created by a double-negative feedback loop.

FIGURE 3.

Model for the pap off-to-on state transition, an example of a bistable switch controlled by DNA methylation patterns. A, in the phase off state, an octamer of Lrp (a tetramer of dimers; only one tetramer is depicted) binds cooperatively to promoter-proximal sites 1–3 (red boxes). Lrp binding to sites 1–3 inhibits further binding of Lrp to sites 4–6 (green boxes) by mutual exclusion. B, immediately following passage of the replication fork (REP 1), the two daughter chromosomes become hemimethylated. Only the daughter chromosome methylated on the top strand is shown (filled circle above Lrp-binding site 5). C, two stochastic events occur in which PapI facilitates Lrp binding to sites 4–6, and Dam (DNA adenine methylase) methylates both strands of the proximal GATC site. Binding of Lrp at sites 4–6 reduces the affinity of Lrp for sites 1–3 by mutual exclusion and facilitates activation of pap transcription via cAMP-catabolite gene activator protein/RNA polymerase binding (not shown). Methylation of GATC^prox reduces the affinity of PapI/Lrp for sites 1–3 and is required for transition to the on phase (98). D, one additional round of DNA replication (REP 2) completes transition to the phase on state, in which GATC^dist is fully unmethylated. The on phase is self-perpetuating due to a bidirectional feedback loop between PapB and PapI (dashed arrow). The PapB level rises due to activation of transcription of the first gene of the pap operon, papB. PapB binds near the papI promoter, increases the PapI level via activation of papI transcription, and helps maintain the on state via binding of PapI/Lrp to sites 4–6.