Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.
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C.D.A. and T.J. are grateful to all of our laboratory members, past and present, and to our scientific colleagues in the field for helping us 'write' the history that we review here. Their hard work, insights and passion for the field of epigenetics have made the last 20 years such an enjoyable ride. We thank P. Jones (Grand Rapids, Michigan, USA) and A. Tarakhovsky (New York, USA) for giving us feedback on this manuscript and M. Onishi-Seebacher (Freiburg, Germany) for help with the figure preparations and reference listings. Our objective in this article is to be more reflective than comprehensive, and admittedly, we have brought forward our personal views. We ask for understanding from those colleagues whose important contributions could not be explicitly mentioned.
The authors declare no competing financial interests.
- Binary switches
The modification of adjacent or nearby histone residues affecting recognition and binding by reader proteins.
- Cellular reprogramming
Conversion of a differentiated cell to an embryonic state.
- Charge effects
The effect of post-translational histone modifications on altering the electrostatic interaction with DNA.
- Enhancer of zeste
(E(z)). Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a histone H3 lysine 27 (H3K27) methylating enzyme.
Enzymes that remove histone modifications from chromatin.
Light-staining, decondensed and transcriptionally accessible regions of the genome.
Dark-staining, condensed and gene-poor regions of the genome.
- Histone cassettes
Short sequences in histone proteins with clustered histone modifications that direct the biological readout in a combinatorial fashion.
A chromatin state defined by whether the gene or genetic locus is inherited from the male or the female germ line.
- Mating-type loci
Genetic elements in yeast containing mating-type information (a or α) that is activated by recombination from heterochromatic copies of one of the two mating-type alleles.
A property in which several histone modifications work together to increase the binding of reader proteins or the stability of a nucleosomal arrangement.
Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a chromodomain-containing methylated histone H3 lysine 27 (H3K27me)-binding factor.
- Position-effect variegation
(PEV). Stochastic and variegated expression of a gene due to juxtaposition to heterochromatic domains.
Proteins that recognize and bind chromatin through histone modification recognition domains.
- SET domain
A 120-amino-acid signature domain for histone lysine methyltransferases (KMTs) that is conserved in Suppressor of variegation 3–9, Enhancer of zeste and Trithorax.
- Silent information regulator proteins
A complex of trans-acting silencing proteins involved in establishing and maintaining heterochromatin in buddingyeast.
- Suppressor of variegation 3–9
(Su(var)3–9). Originally identified in genetic screens for position effect variegation in Drosophila melanogaster and later shown to encode a histone H3 lysine 9 (H3K9) methylating enzyme.
- Topologically associated domains
(TADs). Large genomic regions promoting regulatory interactions by forming higher-order chromatin structures separated by boundary regions.
- Transgenerational inheritance
Transmission of epigenetic information that is passed on to gametes without alteration of the DNA sequence.
Originally identified in genetic screens for homeotic transformations in Drosophila melanogaster and later shown to encode a histone H3 lysine 4 (H3K4) methylating enzyme.
Enzymes that add histone modifications to chromatin.
- X-chromosome inactivation
A process in which one of the two X chromosomes is randomly inactivated in female mammalian cells early in development.
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Allis, C., Jenuwein, T. The molecular hallmarks of epigenetic control. Nat Rev Genet 17, 487–500 (2016). https://doi.org/10.1038/nrg.2016.59
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