A recent article in The Smithsonian Magazine (Doudna 2023) by Nobel Laureate Jennifer Doudna described seminal contributions of Barbara McClintock. Armed with a Bausch and Lomb microscope, maize, and an unflagging spirit of joyful curiosity, McClintock famously discovered that genes could jump between different locations in the genome. Her work overturned the prevailing dogma that DNA was impervious to large-scale change. In fact, transposition is just one arrow in the arsenal of modifiers that an organism has at its disposal, allowing it to react to external cues and internal threats and to follow specific developmental fates. In the 40 years, since McClintock won the Nobel Prize for her work, the chromosome biology field has discovered that genome folding, regulators such as histones and transcription factors, and even the act of transcribing RNA from the genome, exist in every imaginable flavor. This special issue “New Voices in Epigenetics” features a range of provocative ideas, new types of tools and data, dedicated to the singular tenet of science that no idea or experiment is sacrosanct and that new data should—and often does—challenge long held assumptions.

First, Lu Gan and Claris Chong tackle the concept of a nucleosome, the fundamental unit of chromatin in eukaryotes. They summarize results which suggest that nucleosomes can sample several degrees of freedom in conformational space. This leads them to provocatively conclude that, in some organisms, nucleosomes are not likely to possess octameric histone configurations, nor even bind a full turn of DNA, thereby, turning the concept of “canonical” nucleosome on its very head. From the functional point of view, they thoughtfully discuss processes which might contribute to chromatin variability and why such flexibility might be advantageous to the genome. Antoine Molaro and Germaine Karam then take us back to the beginning—to gametogenesis. The review probes recent origins of evolutionary divergent histone variants which regulate female and male gametogenesis. These fascinating histones include ultra-short H2A variants, which are expressed during early male meiosis, encoding highly unstable nucleosomes, preceding the temporal window when protamines replace histones genome-wide during sperm maturation. Interestingly, short H2As are also implicated in cancer progression, suggesting a plausible link between conformational stability of nucleosomes and epigenetic fate. In this vein, Lu Bai and colleagues ask how transcription factors (TFs) control epigenetic fate, by finding specific gene targets buried within thousands of DNA recognition motifs in the genome. They compare the efficacy and accuracy of existing genome-wide profiling tools used to assess TF binding and chromatin accessibility. They highlight a bold strategy: the introduction of synthetic DNA into specific loci in living cells. These DNA tags can act as a read-out to capture the full range of dynamic actions on the chromatinized template by fluorescent reporters, be used for active disruption of enhancer-promoter interactions, and even illuminate what happens at untranslated regions of genes. In the era of CRISPR pioneered by Doudna and Charpentier, they make a compelling argument that such a strategy can effectively be used to spy on the genome in virtually any organism of choice. Rifka Vlijm and Thomas Burgers take this idea one step further, demonstrating how powerful super-resolution microscopes can be used to interrogate these processes at the nanometer scale within living cells. The review explains how these microscopes can bypass the diffraction limit of light, emphasizes the use of multi-color fluorophore labeling, and carefully discusses the strengths and caveats of various super-resolution microscopy approaches. Karen Yuen and colleagues review how live imaging can break barriers in visualizing noncoding RNAs arising from repetitive DNA elements at centromeres and pericentromeric heterochromatin. They explore how noncoding RNAs, despite their evolutionary divergence and indeterminate structure, play a critical part in the faithful restoration of epigenetic identity in the genome. In the last article, Daniel Arango and colleagues discuss an emergent topic in nuclear biology: post-transcriptional RNA modifications. These chemical signals regulate messenger RNA stability, maturation, processing, and even efficacy of translation by the ribosomal machinery. They speculate on the unexplored potential of such chemical modifications on noncoding and chromatin-associated structural RNAs, which could contribute to the binding and recognition of these RNAs by various effector complexes.

These articles by talented early and mid-career researchers encompass a fraction of creative ideas and cutting-edge tools that represent the new frontiers of chromosome biology. The curiosity and excitement that are evident in these reviews can be paraphrased elegantly in a quote borrowed from the irrepressible McClintock (Keller 1984): “It never occurred to me that there was going to be any stumbling block,” she recalled. “Not that I had the answer, but [I had] the joy of going at it. When you have that joy, you do the right experiments. You let the material tell you where to go, and it tells you at every step what the next has to be.”