Neuroepigenetics 2 (2015) 9–12

Contents lists available at ScienceDirect

Neuroepigenetics

journal homepage: www.elsevier.com/locate/nepig

Keystone Symposia on Neuroepigenetics—bridging the gap between genome and behavior

Francesca Telese

Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA article info abstract

Article history: The Keystone Symposium on Neuroepigenetics (Santa Fe, NM, USA, February 22–26, 2015) brought together Received 20 April 2015 outstanding researchers to discuss their latest findings in the field of epigenetic regulation of Accepted 1 May 2015 in the . This has been the first conference entirely devoted to the integration of the fields of and neuroscience. The goal of the symposium was to raise new challenging questions and to Keywords: stimulate innovative ideas fostered by the provocative results presented by experts working in a wide Epigenetics array of epigenetic systems and generated by a variety of experimental approaches in many model systems. Neuroscience Sequencing This report will discuss a number of groundbreaking discoveries presented at the symposium encompassing Behavior studies of human evolution, nervous system development, adult plasticity, transgenerational inheri- tance, mental disorders, and large-scale efforts to generate detailed reference epigenomes. The outcome of the symposium provided new exciting perspectives and the framework for expanding the frontiers of neuroscience research. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction during an exciting 3-day agenda. The symposia was a tremendous success supported by NIH Director's Fund and organized by In recent years, epigenetics has emerged as one of the most rapid- Hongjun Song (Johns Hopkins University, USA) and Li-Huei Tsai ly expanding and dynamic research areas in biology that investigates (Massachusetts Institute of Technology, USA); the program that these the genome function in the regulation of an impressive diversity of 2 leading researchers developed and their selection of presenters cellular processes in homeostasis and disease (Sweatt, 2013). Al- were key to meet the goal of pushing the boundaries in the emerging though the genomic sequence of many organisms has been complet- field of neuroepigenetics. ed, understanding how DNA sequences are deciphered in the context fi of individual cell types or speci c environmental conditions repre- Keynote session sents the fundamental question of epigenetics. Tremendous advances in massively parallel sequencing techniques have revolutionized the Two leading pioneers of the field delivered the first keynote ses- fi eld of epigenetics, and large-scale epigenomic projects, such as the sion: Fred H. Gage (The Salk Institute for Biological Studies, USA) Encyclopedia of DNA Elements (Stamatoyannopoulos, 2012)and and Micheal E. Greenberg (Harvard Medical School, USA). Fred the NIH Epigenomic Roadmap (Bernstein et al., 2010), have been in- Gage described his journey in studying the role of transposable ele- strumental in identifying the functional elements of the genome and ments in human evolution by identifying the molecular differences their contribution to human diseases by generating detailed maps of between human and nonhuman primates based on cutting-edge chromatin states of distinct cell types and tissues. Because epigenetic techniques that incorporate high-throughput sequencing mechanisms play central roles in many neuronal processes, a epigenomic approaches with the establishment of induced pluripo- deeper understanding of distinct epigenetic signatures of the neu- tent stem cells (iPSCs) from human, chimpanzee, and bonobo. Com- ronal genome also has the potential to tackle their deregulation parative gene expression analysis of specie-specific iPSCs revealed into a broad spectrum of brain diseases (Telese et al., 2013). differences in the regulation of long interspersed element 1 (LINE- These and other aspects of epigenetics research were addressed at 1) transposons, which are the only known active transposons in the the Keystone Symposia on Neuroepigenetics. The conference fea- human genome (Marchetto et al., 2013). Recent findings from Gage's tured a diverse group of outstanding scientists, including plenary laboratory and others indicated that those elements are expressed fi speakers and junior researchers, reporting their latest ndings not only in the germ line but also in the brain, challenging the dogma that the genome of postmitotic neurons is static and suggest- E-mail address: [email protected]. ing that they drive genetic heterogeneity across neurons in the same

http://dx.doi.org/10.1016/j.nepig.2015.05.001 2214-7845/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 10 F. Telese / Neuroepigenetics 2 (2015) 9–12 individual and, therefore, they might have a role in dictating individ- Epigenetic mechanisms in regulating synapse formation, plasticity, ual behavior and contributing to vulnerability to disease (Guffanti and behavior et al., 2014; Kazazian, 2004; Muotri et al., 2005). In his inspiring talk, Fred Gage presented sequencing data to identify novel Long-standing themes such as regulation of synaptic plasticity nonreference L1 insertions and provided evidence that LINE-1 repeats were included in the program, and various talks proposed novel view- exhibit different mobility in nonprimate compared to humans, points in the molecular mechanisms underlying cognitive functions. A supporting the hypothesis that LINE-1 transposition could be consid- novel perspective was offered by Li-Huei Tsai, who has dedicated her ered as potential driver of genomic innovation underlying adaptive career to elucidate molecular and cellular mechanisms of cognition changes in evolution. Given that epigenetic mechanisms, such as with particular emphasis on models of Alzheimer disease. She pre- DNA , are crucial to control the mobilization of transpos- sented her latest findings in the regulation of immediate early genes, able elements in the genome, the study of epigenetic regulation of which involves generation of DNA double strand breaks within their their mobility has major implications in all areas of neuroscience promoters to relieve a topological constraint that imposes another (Erwin et al., 2014). layer of regulation in the fast response of neurons to experience- The second lecture by Michael Greenberg focused on his career- dependent changes. This provocative finding inspired questions re- long research interest regarding the function of gene expression pro- garding mechanisms of DNA repair in postmitotic neurons and might grams activated by neuronal activity at the level of synapses and have major implications in the study of neurodegenerative pathways. transduced into the nucleus by signaling molecules that ultimately David Sweatt (University of Alabama at Birmingham, USA) pre- target transcription factors and chromatin regulators (West and sented his recent work on novel mechanisms of epigenetic regulation Greenberg, 2011). The most intriguing aspect of his presentation of associative conditioning that involve recently identified was his recent work on the misregulation of long gene expression extracoding RNAs, suggesting that neuronal activity-dependent tran- in the brain when MECP2 is mutated in human or mouse models of scription modulates DNA methylation (Di Ruscio et al., 2013). Those Rett syndrome (Gabel et al., 2015). Combining genomic profiling of noncoding RNA molecules are generated from coding genes and MeCP2 and genome-wide base pair resolution DNA methylation as- have the ability to block DNA methylation events by forming second- says, it emerged that MECP2 represses long genes by binding to a ary structures that interact with the methyltransferase DNMT1. By form of methylated DNA enriched in the brain. Because the long using deep sequencing approaches to profile the transcriptome and genes repressed by MeCP2 are enriched in functional annotation of methylome of neuronal cultures, it emerged that the presence of neuronal functions, Michael Greenberg proposed the idea that dis- extracoding RNAs may predict gene-specific methylation status. This ruption of long gene expression might be a general mechanism un- epigenetic mechanism is involved in the regulation of associative con- derlying the neurological dysfunctions in Rett syndrome. It was ditioning in the hippocampus, as demonstrated by altered learning be- exciting to hear how the inhibition of topoisomerases with haviors of mice previously injected with antisense oligos interfering topotecan, a drug commonly used as a chemotherapeutic agent, with specific extracoding RNAs. leads to a dose-dependent reversal of long gene expression, which In addition, this session highlighted novel groundbreaking dis- inspired novel ideas for developing methods to rebalance long coveries in the epigenetic regulation of synaptic and behavioral gene expression as a strategy to correct neural dysfunction in plasticity mediated by methylation events that dynamically target neurodevelopmental disorders. both DNA and RNA. Particularly, Hongjun Song covered the mech- anisms of neuronal activity-induced active DNA demethylation pathways that involve TET enzymatic machineries to convert 5- Epigenetic mechanisms in reprogramming methylcytosine to 5-hydroxylmethylcytosine. Tet3 expression is dynamically regulated by synaptic activity and in turn effects ex- Induced pluripotent stem cell technology represents one of citatory glutamatergic transmission by modulating the amount the major advances in modeling of neurological disorders of surface GluR1 at a transcriptional level (Yu et al., 2015). Timo- in vitro (Nityanandam and Baldwin, 2015). iPSC-derived neurons thy Bredy (Queensland Brain Institute, Australia) talked about represent a powerful strategy for elucidating disease pathogene- RNA modifications, such as N6-methyladenosine, as a crucial sis for drug discovery and development, for personalized medi- epigenetic mechanism in the fine tuning of gene expression related cine, and eventually for regenerative cell therapy, as suggested to adaptation. by many talks and posters presented at this meeting. However, The increasing amount of epigenetic modifications associated to the standard transdifferentiation protocol, which relies on the experience-dependent changes in the brain and linking epigenetic forced expression of neural lineage–specific transcription factors, alterations to development of neurological disorders provoked fer- is a long process with multiple steps that might increase the het- tile discussions regarding epigenetic modifications as potential tar- erogeneity of the final neuronal population. In this context, Xiang- gets for drug treatment. Jeffrey S. Ney (Janssen R&D/Johnson and Dong Fu (University of California, San Diego, CA, USA), a leader in Johnson Innovation, Cambridge, MA, USA) portrayed the latest ad- the research area of RNA splicing, presented his recent work on an vances in the translational use of neuroepigenetic discoveries as innovative and fast method for direct conversion of somatic cells epigenetic therapies for brain disorders. It emerged that combining to functional neurons based on repressing the expression of a single genomic sequencing and expression data might represent a critical RNA binding protein, PTB (Xue et al., 2013). Researchers led by strategy to better define the druggable epigenomes. Although Xiang-Dong Fu elucidated the molecular feedback loops that modu- many of the epigenetic drugs hold great promises, such as HDAC late the repression of PTB during neuronal differentiation when a inhibitors as treatment for cognitive impairments, many challenges microRNA-regulated splicing event causes the switch to the are still unsolved, such as efficient delivery through the blood-brain neuronal-specific isoform of PTB. barrier, safety, and tolerability for chronic treatments. Many discussions at this meeting pivoted on the urgent need of efficient protocols for transdifferentiation to specific neuronal sub- Molecular mechanisms types and supported the notion that the epigenomic profiling of these cells is a crucial strategy for mechanistic characterization of Experts in the field of epigenetics presented their overview of these cells and for developing novel protocols. how diverse signaling transduction pathways affect behavioral F. Telese / Neuroepigenetics 2 (2015) 9–12 11 processes by modulating epitranscriptomic events. Michael G. tissues and cell types (Roadmap Epigenomics et al., 2015). This inte- Rosenfeld (University of California, San Diego, CA, USA) presented grative analysis was based on the global profile of modifica- his latest findings unraveling unexpected roles of enhancers as tran- tions, DNA methylation, DNA accessibility, and RNA expression, scription units, global roles of noncoding RNAs, and dynamic changes along with genome-wide association studies, linking disease and in nuclear architecture in model systems relevant to , develop- trait-associated genetic variants to tissue-specificepigenomic ment, aging, and brain plasticity (Liu et al., 2014; Puc et al., 2015; marks. By applying this strategy to a mouse model of Alzheimer dis- Skowronska-Krawczyk et al., 2014). His laboratory identified the ease, a team from Manolis Kellis and Li-Huei Tsai's groups demon- epigenomic signature underlying learning and memory processes ac- strated that genetic variants associated with the disease are tivated by the Reelin signaling pathway, which is associated with enriched in evolutionary conserved regulatory enhancers that control many neuropsychiatric disorders. The LRP8-Reelin-regulated en- immune response genes linked to inflammation, but not neuronal hancers orchestrate the transcriptional changes occurring during hip- pathways (Gjoneska et al., 2015). These intriguing results suggest pocampal associative learning and memory formation as a that the immune functions might be the major contributor to genetic consequence of a novel synapse-to-nucleus signaling involving the predisposition to Alzheimer disease, whereas the cognitive decline γ-secretase–dependent release of the LRP8 intracellular domain could be linked to nongenetic environmental factors and identified that serves as a messenger molecule to transduce synaptically gener- new factors that could become novel therapeutic targets. ated signals in the nucleus (Telese et al., 2015). Joseph R. Ecker delivered a retrospective that illustrated the great Paolo Sassone-Corsi (University of California, Irvine, USA) illus- advances in the exploration of mammalian methylomes based on trated a comprehensive picture of his long-lasting interest in novel whole genome bisulfite sequencing assays developed in his deciphering the epigenetic language of the circadian clock (Asher laboratory at The Salk Institute for Biological Studies, USA (Urich and Sassone-Corsi, 2015). He presented his latest findings regarding et al., 2015). The genome-wide, base-resolution, DNA methylomes the oscillatory changes in gene expression as a strategy of epigenomic profiling has been pivotal in studying the widespread reconfiguration regulation of the circadian rhythm. In the most inspiring part of his of methylation events occurring during development of frontal cortex talk, Paolo Sassone-Corsi described a novel link between energy me- (Lister et al., 2013). Joseph Ecker addressed a major challenge by an- tabolism, epigenetics, and the circadian clock, showing how the cellu- alyzing relatively homogenous populations of distinct neuronal sub- lar metabolic processes in response to nutrients are intimately linked types through an innovative purification approach that allowed the to processes through cross-talk mechanisms identification of specific DNA methylation dynamics, which is key to that involve NAD+-mediated metabolism, histone posttranslational unravel the epigenetic mechanisms essential for maturation and modifications, and enzymatic feedback loops mediated by the his- maintenance of distinct neuronal identities. tone deacetylases and histone methyltransferase (Aguilar-Arnal It was clear that profiling cell type–specificanddiseasestate–spe- et al., 2015). cific epigenomic landscapes has a critical importance in understand- The talk from Isabelle Mansuy (Brain Research Institute, ETH Zurich, ing of how epigenetic changes can contribute to or drive neuronal Switzerland) focused on transgenerational epigenetics, a topic that has identity and human disease. recently attracted both interest and debate in the field by proposing epigenetic changes as a candidate mechanism to explain how an organ- Workshop: high-throughput sequencing for neuroepigenetics ism can transmit learned behaviors or traits to its offspring (Heard and Martienssen, 2014). By using an experimental model of early traumatic Remarkable presentations were given during the highly informa- stress in mice, she provided evidence that traumatic events, such as un- tive workshop focused on the application of high-throughput predictable maternal separation and maternal exposure to stress, can sequencing methods to address fundamental questions in neurosci- fl strongly in uence the behaviors of the offspring inducing depressive ence. Particular emphasis was dedicated to the development of behaviors and cognitive dysfunction across several generations (Gapp novel computational frameworks to elucidate complex epigenomic fi et al., 2014b). She presented her latest ndings indicating that these regulatory circuitries and to the epigenomic profiling of iPSCs as a phenomena are transmitted across generations thorough male sperms strategy for modeling brain diseases. and are associated with 3 potential nongenetic mechanisms: DNA As part of the Roadmap Epigenomics Program, Michael J. Ziller fi methylation of CpG islands of several genes, post-translational modi - (Broad Institute of MIT and Harvard, USA) presented his extensive cations of histone tails, and altered expression of noncoding RNAs work on uncovering the epigenomic plasticity during neuronal differ- (Gapp et al., 2014a). The challenge remains to provide evidence for entiation (Ziller et al., 2015). By integrating DNA methylation assays, the causality link between epigenetic changes in sperm cells and behav- chromatin immunoprecipitation, and gene expression analysis, Mi- ioral effects across generations. chael Ziller identified the epigenetic footprint distinguishing each cell state transition based on the progressive remodeling of the epige- Epigenomes netic landscape. Each differentiation stage was linked to the combi- natorial actions of specific transcription factors, which was revealed The need of finding the right intersections between traditional by the novel computational framework ( epige- approaches that have been instrumental in studying neuronal func- netic remodeling activity) based on the assessment of DNA binding tions, such as cellular and behavioral studies of various genetic motifs associated with distinct epigenetic states. This approach was models, and fine mechanistic insights provided by the plethora of decisive to shed light on regulatory mechanisms of cell fate decisions “omic” strategies was extensively covered by researchers at the fore- of neuronal development but also represents a general computation- front of this field, which illustrated the rapid advances and unique al strategy for the systematic discovery of the epigenomic changes in opportunities delivered by large-scale projects of relevance to the a variety of biological systems. neuroscience community (Romanoski et al., 2015). The topic of modeling neurodevelopmental disorders by integrat- Manolis Kellis (Broad Institute of MIT and Harvard) presented ing epigenomic tools with iPSCs was presented by Matthew A. Lalli, a some of the landmark achievements of the NIH Roadmap graduate student from the University of California Santa Barbara, Epigenomics Mapping Consortium, a public resource of reference USA. In his work, Matthew Lalli integrated global gene expression epigenomes that provide information on how key genomic regulato- profiling of Williams syndrome–induced pluripotent neurons with ry elements orchestrate gene expression patterns in 127 human genomic distribution by ChIP-seq of one of the genes deleted in 12 F. Telese / Neuroepigenetics 2 (2015) 9–12

Williams syndrome. His findings elucidate the epigenomic changes Gabel, H.W., Kinde, B., Stroud, H., Gilbert, C.S., Harmin, D.A., Kastan, N.R., et al., 2015. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. that are likely to contribute to the cognitive and behavioral pheno- Nature. types of the disorder, providing compelling evidence that the Gapp, K., Jawaid, A., Sarkies, P., Bohacek, J., Pelczar, P., Prados, J., et al., 2014a. Implica- epigenomic profiling of iPSCs represents a powerful tool for modeling tion of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669. brain diseases and holds great promise for revealing cellular and be- Gapp, K., Soldado-Magraner, S., Alvarez-Sanchez, M., Bohacek, J., Vernaz, G., Shu, H., et al., havioral phenotypes associated to patient-specific mutations. 2014b. Early life stress in fathers improves behavioural flexibility in their offspring. Nat. Commun. 5, 5466. Gjoneska, E., Pfenning, A.R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.H., et al., 2015. Highlights from poster presentations Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature 518, 365–369. Exciting poster presentations covered all the aspect of Guffanti, G., Gaudi, S., Fallon, J.H., Sobell, J., Potkin, S.G., Pato, C., et al., 2014. Transposable neuroepigenetics. Michael Corley, who was awarded with the elements and psychiatric disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B, 201–216. NIGMS Ancillary Training Program Scholarship for this conference, Heard, E., Martienssen, R.A., 2014. Transgenerational epigenetic inheritance: myths presented a remarkable study carried out in the laboratory of Alika and mechanisms. Cell 157, 95–109. Maunakea (Epigenomics Research Program of University of Hawai'i, Kazazian Jr., H.H., 2004. Mobile elements: drivers of genome evolution. Science 303, 1626–1632. USA), who was also a recipient of the Early-Career Investigator Travel Lister, R., Mukamel, E.A., Nery, J.R., Urich, M., Puddifoot, C.A., Johnson, N.D., et al., 2013. Award. Their work focused on the comparative DNA methylomic Global epigenomic reconfiguration during mammalian brain development. analyses of the neurogenic subventricular zone from autism spec- Science 341, 1237905. – Liu, Z., Merkurjev, D., Yang, F., Li, W., Oh, S., Friedman, M.J., et al., 2014. acti- trum disorder diagnosed postmortem , revealing substantial vation requires trans-recruitment of a mega transcription factor complex. Cell autism spectrum disorder–specific alterations of DNA methylation, 159, 358–373. with a stronger correlation with embryonic and neural stem cell– Marchetto, M.C., Narvaiza, I., Denli, A.M., Benner, C., Lazzarini, T.A., Nathanson, J.L., et al., fi 2013. Differential L1 regulation in pluripotent stem cells of humans and apes. speci c methylation states, providing novel evidence in support of Nature 503, 525–529. the hypothesis that molecular alterations associated with autism Muotri, A.R., Chu, V.T., Marchetto, M.C., Deng, W., Moran, J.V., Gage, F.H., 2005. Somatic arise early in development. mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910. On a similar topic, Eran Mukamel (University of California, San Nityanandam, A., Baldwin, K.K., 2015. Advances in reprogramming-based study of Diego, USA) presented his work focused on novel genetic strategies neurologic disorders. Stem Cells Dev. to isolate distinct cortical neuron cell types, such as parvalbumin- Puc, J., Kozbial, P., Li, W., Tan, Y., Liu, Z., Suter, T., et al., 2015. Ligand-dependent – expressing fast-spiking interneurons and vasoactive intestinal enhancer activation regulated by topoisomerase-I activity. Cell 160, 367 380. Roadmap Epigenomics, C., Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., et al., peptide–expressing interneurons. Transcriptome and whole- 2015. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330. genome methylome profiling revealed cell type–specificpatternsof Romanoski, C.E., Glass, C.K., Stunnenberg, H.G., Wilson, L., Almouzni, G., 2015. – non-CG methylation that covary with gene transcription across corti- Epigenomics: roadmap for regulation. Nature 518, 314 316. Skowronska-Krawczyk, D., Ma, Q., Schwartz, M., Scully, K., Li, W., Liu, Z., et al., 2014. cal neuron types. His approach provides a valid tool to study the epi- Required enhancer-matrin-3 network interactions for a homeodomain transcription genetic regulatory networks necessary to develop and maintain program. Nature 514, 257–261. distinct neuronal identities. Stamatoyannopoulos, J.A., 2012. What does our genome encode? Genome Res. 22, 1602–1611. Sweatt, J.D., 2013. The emerging field of neuroepigenetics. Neuron 80, 624–632. Closing remarks and future perspectives Telese, F., Gamliel, A., Skowronska-Krawczyk, D., Garcia-Bassets, I., Rosenfeld, M.G., 2013. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron 77, 606–623. Apart from advancing our understanding of epigenetic mecha- Telese, F., Ma, Q., Perez, P.M., Notani, D., Oh, S., Li, W., et al., 2015. LRP8-Reelin-regulated nisms of neuronal function and dysfunction, the symposium cut across neuronal (LRN) enhancer signature underlying learning and memory formation. boundaries of molecular biology and classical behavioral neuroscience Neuron 86, 1–15. Urich, M.A., Nery, J.R., Lister, R., Schmitz, R.J., Ecker, J.R., 2015. MethylC-seq library and provided a spirited discussion forum for promotion of cross- preparation for base-resolution whole-genome bisulfite sequencing. Nat. Protoc. disciplinary collaborations between investigators that normally may 10, 475–483. not readily interact. Attendees of the symposium enthusiastically West, A.E., Greenberg, M.E., 2011. Neuronal activity-regulated gene transcription in synapse development and cognitive function. Cold Spring Harb. Perspect. Biol. 3. agreed that this meeting provided an important context for the com- Xue, Y., Ouyang, K., Huang, J., Zhou, Y., Ouyang, H., Li, H., et al., 2013. Direct conversion munication and exchange of ideas that will have a major role in of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell influencing the direction of research in this field. Moving forward, 152, 82–96. the integration of innovative sequencing technologies, big data analy- Yu, H., Su, Y., Shin, J., Zhong, C., Guo, J.U., Weng, Y.L., Gao, F., Geschwind, D.H., Coppola, G., Ming, G.L., et al., 2015. Tet3 regulates synaptic transmission and homeostatic ses, disease modeling with iPSCs, and classical genetic and behavioral plasticity via DNA oxidation and repair. Nat. Neurosci. studies will provide a fertile ground for discoveries that will impact the Ziller, M.J., Edri, R., Yaffe, Y., Donaghey, J., Pop, R., Mallard, W., et al., 2015. Dissecting basic understanding of neuronal function and catalyze new diagnostic neural differentiation regulatory networks through epigenetic footprinting. Nature 518, 355–359. and therapeutic strategies in disease.

References

Aguilar-Arnal, L., Katada, S., Orozco-Solis, R., Sassone-Corsi, P., 2015. NAD(+)-SIRT1 Francesca Telese obtained an MS in Medical Biotechnolo- control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat. gy and a PhD in Neuroscience from the University of Na- Struct. Mol. Biol. 22, 312–318. ples “Federico II” (Naples, Italy). After her doctoral Asher, G., Sassone-Corsi, P., 2015. Time for food: the intimate interplay between nutri- studies, she joined the laboratory of Prof Michael G. tion, metabolism, and the circadian clock. Cell 161, 84–92. Rosenfeld, an internationally recognized leader in the Bernstein, B.E., Stamatoyannopoulos, J.A., Costello, J.F., Ren, B., Milosavljevic, A., field of epigenetic control of gene transcription. Her re- Meissner, A., et al., 2010. The NIH Roadmap Epigenomics Mapping Consortium. search interest in the field of neuroepigenetics is focused Nat. Biotechnol. 28, 1045–1048. on understanding how gene regulatory networks ulti- Di Ruscio, A., Ebralidze, A.K., Benoukraf, T., Amabile, G., Goff, L.A., Terragni, J., et al., mately drive complex neurobiological processes by iden- 2013. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature tifying the epigenomic signatures underlying functional 503, 371–376. pathways relevant to cognition and brain disease. Erwin, J.A., Marchetto, M.C., Gage, F.H., 2014. Mobile DNA elements in the generation of diversity and complexity in the brain. Nat. Rev. Neurosci. 15, 497–506.