Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

Abstract

Alternative non‐B‐DNA conformations formed under physiological conditions by sequences called flipons include left‐handed Z‐DNA, three‐stranded triplexes, and four‐stranded i‐motifs and quadruplexes. These conformations accumulate and release energy to enable the local assembly of cellular machines in a context specific manner. In these transactions, nucleosomes store power, serving like rechargeable batteries, while flipons smooth energy flows from source to sink by acting as capacitors or resistors. Here, I review the known biological roles for flipons. I present recent and unequivocal findings showing how innate immune responses are regulated by Z‐flipons that identify endogenous RNAs as self. Evidence is also presented supporting important roles for other flipon classes. In these examples, the dynamic exchange of energy between flipons and nucleosomes enables rapid switching of genetic programs without altering flipon sequence. The increased phenotypic diversity enabled by flipons drives their natural selection, with adaptations evolving faster than is possible by codon mutation alone.

Z-flipon variants reveal the many roles of Z-DNA and Z-RNA in health and disease

“…The energy necessary to power the flip from B-DNA to Z-DNA inside cells can be generated by RNA polymerases and helicases during transcription or by the ejection of nucleosomes from DNA. Flipon base modifications or interactions with noncoding RNAs can further modulate the dynamics of Z-DNA formation ( Herbert, 2022 ; Herbert et al, 2023 ).…”

“…We used a machine learning approach called Z-DNABERT to detect Z-flipons by tuning the transformer algorithm implemented in DNABERT ( Ji et al, 2021 ) with experimentally validated Z-DNA-forming sequences obtained from the human genome. By conjointly using a variety of predictive and experimental methods, we were able to show Z-flipons are enriched in promoters where they can catalyze the turnover of protein complexes involved in transcription ( Herbert, 2022 ).…”

“…Overall, there was enrichment of Z-flipons in promoters. The presence of multiple flipons in many promoters suggest that promoter conformation is quite variable with the partitioning of energy between B- and Z-DNA leading to many different shape combinations ( Herbert, 2022 ). The potential of repeats like d(CGGG) n to adopt both Z-DNA and G4-quadruplex conformation adds an additional level of complexity.…”

“…The results we describe here are consistent with a model where ZNAs localize proteins to a site where they act. In the nucleus, Z-DNA can catalyze the turnover of the cellular machinery at promoters to regulate gene transcription as evidenced in a number of previous studies (reviewed in Herbert [2021a] and [ 2022 ]). The chromatin structures and condensates formed, some of which may be based on the Z-RNA motifs described here ( Figs 5 – 7 ), enable approximation of distant regions through loop formation independently of loop extrusion ( Fudenberg et al, 2016 ).…”

Z-Flipons conserved between human and mouse are associated with increased transcription initiation rates

“…H2A.Z overlap more than half (63% and 66%) of DeepZ conserved regions in mouse and human. Almost all CpG-promoters with Z-flipons (97% in human and 99% in mouse) are marked with H2A.Z which interestingly plays a role in neuronal activity and differentiation 34,35 and has a lysine/alanine dipeptide repeat that can dock to Z-DNA 36 . The acetylation of this variant H2A.Zac is higher in mouse compared to human (94% vs 77% at CpG-promoters); it activates neo-enhancers in prostate cancer 37,38 and plays a role in trophoblast differentiation in human embryonic stem cells 39 .…”