Waddington’s Landscapes in the Bacterial World

Abstract

Conrad Waddington’s epigenetic landscape, a visual metaphor for the development of multicellular organisms, is appropriate to depict the formation of phenotypic variants of bacterial cells. Examples of bacterial differentiation that result in morphological change have been known for decades. In addition, bacterial populations contain phenotypic cell variants that lack morphological change, and the advent of fluorescent protein technology and single-cell analysis has unveiled scores of examples. Cell-specific gene expression patterns can have a random origin or arise as a programmed event. When phenotypic cell-to-cell differences are heritable, bacterial lineages are formed. The mechanisms that transmit epigenetic states to daughter cells can have strikingly different levels of complexity, from the propagation of simple feedback loops to the formation of complex DNA methylation patterns. Game theory predicts that phenotypic heterogeneity can facilitate bacterial adaptation to hostile or unpredictable environments, serving either as a division of labor or as a bet hedging that anticipates future challenges. Experimental observation confirms the existence of both types of strategies in the bacterial world.

Pervasive transcription enhances the accessibility of H-NS-silenced promoters and generates bistability in Salmonella virulence gene expression

“…This study adds elongation of pervasive transcripts to the set of mechanisms that produce transcriptional noise (63) and provides a model to understand the molecular basis of SPI-1 bistability, which has remained a longstanding mystery in Salmonella biology. The model fits well in the view that stochastic cell-to-cell differences perpetuated by feedback loops can generate phenotypic lineages (64, 65).…”

Differential adenine methylation analysis reveals increased variability in 6mA in the absence of methyl-directed mismatch repair

“…For a broader view of the factors that influence GATC methylation and to determine if hypomethylation was associated with GATC sites that may be shielded by protein binding, we looked at sites within intergenic regions where DNA-protein interactions likely occur, such as sigma factor binding sites and binding sites of other transcriptional regulatory proteins 10,36,37,52,53 . Overall, within these intergenic regions, there is a general decrease in methylation around promoters.…”

“…6mA influences varied processes including, but not limited to, replication timing, transposon mobility, gene expression, virulence, and methyl-directed mismatch repair (MMR) 9,14,24–35 . Many of these phenotypes occur as bistable states where stochasticity affects methylation status (methylated, unmethylated, or hemimethylated) at a regulatory locus, and proteins that preferentially bind based on methylation status maintain that status as a positive feedback loop 36 . One example of bistability under control of 6mA is the pap operon in uropathogenic E. coli which encodes adhesive fimbriae during infection 37,38 .…”

The red thread between methylation and mutation in bacterial antibiotic resistance: How third-generation sequencing can help to unravel this relationship

“…This effect occurs because during DNA replication methyltransferases use each strand as a stamp for the methylation of the newly synthesized DNA daughter strands. Thus, the motif on the methylated strand will be inherited as methylated, while the other as unmethylated (Sánchez-Romero and Casadesús, 2021 ). This phenomenon can generate bacterial populations genetically identical but with heterogeneous methylation patterns.…”