REVIEWS Eusocial insects as emerging models for behavioural epigenetics Hua Yan1*, Daniel F. Simola2,3*, Roberto Bonasio2,3, Jürgen Liebig4, Shelley L. Berger2,3,5,6 and Danny Reinberg1,7 Abstract | Understanding the molecular basis of how behavioural states are established, maintained and altered by environmental cues is an area of considerable and growing interest. Epigenetic processes, including methylation of DNA and post-translational modification of histones, dynamically modulate activity-dependent gene expression in neurons and can therefore have important regulatory roles in shaping behavioural responses to environmental cues. Several eusocial insect species — with their unique displays of behavioural plasticity due to age, morphology and social context — have emerged as models to investigate the genetic and epigenetic underpinnings of animal social behaviour. This Review summarizes recent studies in the epigenetics of social behaviour and offers perspectives on emerging trends and prospects for establishing genetic tools in eusocial insects. 1Department of Biochemistry Animal behaviour is best understood as an emergent phenotypic states through transcriptional regulation of and Molecular phenomenon predicated on the dynamic interpretation genome-wide gene expression4,7–9. The first strategy is Pharmacology, New York University School of Medicine. of sensory stimuli by the brain. The brain’s response to the use of specific transcription factor (TF) complexes 2Department of Cell and sensory stimuli can be modulated by metabolic pro- and regulatory networks that involve feedback loops Developmental Biology, cesses and the endocrine system1; however, one of the (that is, trans epigenetics), and the second strategy Perelman School of Medicine, most remarkable characteristics of the brain is the abil- involves alteration of chromatin structure through DNA University of Pennsylvania. ity to condition consistent behavioural responses on the methylation, histone post-translational modifications 3 Epigenetics Program, University of Pennsylvania. basis of prior sensory experience. In other words, (PTMs), non-coding RNAs (ncRNAs) and associated 4School of Life Sciences, the architecture of an animal brain encodes a persistence chromatin regulatory proteins (that is, cis epigenetics). Arizona State University, or memory (which is broadly defined here to include all These two processes are able to provide an explanation Tempe, Arizona short- and long-term forms of memory2) of transient for behavioural persistence and plasticity (that is, alter- 85287–4501, USA. sensory stimuli that is used to tune the brain’s sensitiv- ing a behavioural response on the basis of new stimuli) 5Department of Biology, University of Pennsylvania. ity to similar stimuli in the future in order to elicit a by their ability to establish and maintain quantitative 6Department of Genetics, fitting behavioural response. Decades of research into control of transcription for long periods of time, either Perelman School of Medicine, the molecular processes that underlie the persistence of across cell divisions or within terminally differentiated University of Pennsylvania, behavioural responses through memory mechanisms cells such as neurons. Philadelphia, Pennsylvania 19104, USA. have shown a key role for the regulation of gene expres- Several animal species have been developed as mod- 7Howard Hughes Medical sion in neurons, which are one of the major cell types els to investigate the various aspects of animal behav- Institute, New York University of the brain2–6. However, the specific regulatory mecha- iour and brain function, including the fruitfly Drosophila School of Medicine, New York, nisms responsible for establishing and maintaining pat- melanogaster for aggression and reproductive behav- New York 10016, USA. terns of neuronal gene expression in response to sensory iour10, mice and rats for learning and memory11, and the *These authors contributed 12 equally to this work. stimuli remain poorly understood, mainly because zebra finch for neurodegeneration and regeneration . Correspondence to J.L., behavioural responses arise from the integration of However, these systems have notable disadvantages for S.L.B. and D.R. stimuli not only from gene-level networks within a neu- genetic and epigenetic studies of behaviour: fruitflies e‑mails: [email protected]; ron but also from networks that integrate the numerous lack key DNA methylation enzymes13; rodents often [email protected]; neurons (and non-neuronal glial cells) within a brain2,6,7. show strong behavioural variation even in standardized [email protected] 14 doi:10.1038/nrg3787 Over the past 30 years, two general strategies have environments ; and birds can be difficult to maintain 15 Published online 9 September emerged from the historically independent field of epi- in a laboratory . Moreover, none of these organisms are 2014 genetics to explain the induction and maintenance of highly social, and they therefore cannot provide suitable NATURE REVIEWS | GENETICS VOLUME 15 | OCTOBER 2014 | 677 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS Social behaviours experimental paradigms for the large variety of complex this end, key aspects of the brain and the central nerv- The interactions among social behaviours seen in other species. By contrast, the ous system, including gross morphology and neuronal individuals of the same species, species-rich group of eusocial insects (including all ants connectivity, have been extensively characterized in for example, collaboration and termites, as well as some bees and wasps) show exemplary eusocial insects, such as the honeybee and within a well-defined group such as a colony of eusocial many of the most fascinating, complex and enigmatic some ant species, and have been shown to vary by mor- 17–21 insects. displays of animal behaviour. phology, age and social context . Furthermore, many Although individual eusocial insects exhibit behav- eusocial insects, especially ants, can be maintained eas- Polyethism iours that reflect ‘simple’ antagonistic or adaptive ily and in large numbers in a laboratory while largely Variation in the allocation of responses (for example, fight or flight)16, they also display preserving their natural social context, which greatly nest-related tasks among (BOX 2) individuals in a colony. much more sophisticated behaviours elicited by coopera- facilitates controlled behavioural analyses . Polyethism typically refers tive interactions among individuals within a social group Polyethism is primarily influenced by two factors: to the special case of or a colony setting, such as nursing, foraging, nest main- caste morphology and age. Caste morphology is speci- age-dependent changes in an tenance, defence and policing. The regulation of such fied during juvenile (that is, larval or nymphal) develop- individual’s behaviour (that is, polyethism queen worker 22,23 age-dependent or temporal cooperative colonial behaviours (that is, (also ment for both and polymorphic castes . polyethism); however, it more known as division of labour)) is a central feature of more Within each caste, behaviour also changes in an age- generally denotes differences advanced forms of sociality (BOX 1) and often involves dependent manner, as seen in the classic transition from in behaviour associated with the strict allocation of behaviours to qualitatively distinct nursing to foraging in honeybees (Apis mellifera)24,25. caste (that is, temporal as well groups of individuals (denoted as castes) that may vary Timing of these behavioural transitions is not necessar- as morphological or physical polyethism). by age or morphology. The existence of behaviourally ily ‘hardwired’ and is often sensitive to dynamic changes specialized castes in particular underscores the relevance in social context, nutrition and physical environment26 of eusocial insects for behavioural epigenetics research. To (FIG. 1a). This intrinsic behavioural plasticity of eusocial insects provides numerous opportunities for experimen- tal manipulation. For example, in honeybees, selectively royal jelly Box 1 | An overview of insect sociality feeding larvae a protein-rich diet that includes induces their development into queens22,23, whereas Part of our fascination with social insects stems from their capacity to learn and execute removing existing nurses from a colony induces forag- 136 complex decisions not only as individuals but also as integrated social groups — a ers to revert to nursing behaviour27 (FIG. 1b). Workers of rare trait in the animal kingdom. Indeed, the best-studied and most sophisticated forms the ant Harpegnathos saltator can mate, obtain reproduc- of social behaviour are highly restricted taxonomically and are mainly, although not gamergates exclusively, found in the eusocial insect orders Hymenoptera (which includes all ants tive status (that is, become ) and function as and some bees and wasps) and Blattodea (which comprises all termites)22,44. Eusociality queens when an existing queen dies or when workers are 28,29 is also found in select species outside insects, including snapping shrimps and naked artificially isolated individually or in groups (FIG. 1b). mole rats. Gamergates can also be reverted to workers both behav- Eusociality is considered to be the most complex form of sociality and is defined as iourally and physiologically by temporary separation the cooperative care of offspring, which are born from reproductive individuals but are from