Current Research Danny Reinberg studies the dynamic processes shaping chromatin structure and channeling transcriptional outcome. The intricate processes establishing the regulated expression of genes in mammalian cells are both astounding, and challenging to investigate. These processes give rise to the distinctive patterns of proteins produced and the distinguishing traits and functions of the various tissues. This specific patterning of gene expression must then be conveyed to daughter cells upon cell division to ensure their identical properties. My laboratory is geared towards understanding the fundamental mechanisms operating to turn genes on and off, extending from the pluripotent embryonic stem cells ESC to the fully differentiated committed cell lineage.
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Danny Reinberg studies the dynamic processes shaping chromatin structure and channeling transcriptional outcome: key to fostering a cellular identity Figure 1. Figure 1. Chromatin serves as a molecular carrier of epigenetic information by molding the genome into transcriptionally active or transcriptionally repressed, inheritable domains. The intricate processes establishing the regulated expression of genes in mammalian cells give rise to the distinctive patterns of proteins produced and the distinguishing traits and functions of the various tissues.
This specific patterning of gene expression must be conveyed to daughter cells upon cell division to ensure their identical properties. Our strategy in investigating these astounding phenomena involves intensive mechanistic analyses performed in vitro and with this information, exploring the integration and functioning of these mechanisms in vivo.
We steadily incorporated increasingly complex biological contexts into our studies over the years and we are now advancing our investigations into the fascinating process of chromatin compartmentalization and its role in gene regulation from embryonic stem cells ESC to cells of a defined lineage. As well, our goal of studying epigenetics in the context of a whole organism is now coming to fruition based on our extensive studies of the eusocial insect, ants.
This inheritance is paramount to maintaining a cellular identity. Below, I describe our recent findings that in several cases arose from distinct systems devised to capture the dynamics of a particular process in action. Polycomb group PcG of epigenetic regulators Key to maintaining genes in a repressed state are the Polycomb group PcG of proteins that function ultimately to compact chromatin. This property is likely pivotal to the restoration of repressed chromatin domains during cell division see Inheriting chromatin domains, below.
Figure 2. EED binding to H3K27me3 results in a conformational change in PRC2 and a substantial increase in its catalytic activity allosteric activation.
Figure 3. We sought to expose the salient features of repressive chromatin domain formation as it occurs in vivo by tracking PRC2 recruitment de novo to chromatin and its subsequent formation of repressive domains. Importantly, by re-constructing PRC2 with an EED mutant that cannot interact with H3K27me3, PRC2 is confined to the strong nucleation sites and cannot spread Figure 4 , underscoring the importance of its allosteric activation in forming extensive, repressive chromatin domains.
The basic scheme of this system is applicable to other processes for which appropriate assays can follow the evolving events. Figure 4.
We approached this anomaly by tracking over time the repercussions to PRC2 chromatin occupation and repressive domain formation when H3K27M is expressed de novo in unexposed cells. Surprisingly, PRC2 is released in a permanently impaired state, suggesting that an irreversible conformation switch is induced by the oncohistone H3K27M, poisoning PRC2 activity.
By following the cascade of events that culminate in this highly defective gene expression profile, we found that active chromatin domains comprising H3K36me2 inappropriately invade the domains normally repressed through PRC2. We are pursuing both of these signatures, PRC2 conformation and proteins interacting with H3K36me2, which may serve as a novel vulnerability for therapeutic intervention.
Inheriting chromatin domains The essence of epigenetics entails those features of chromatin other than DNA that are inherited during cell division, preserving the integrity of the gene expression profile inherent to a specific cell type.
Yet, which, if any, of the many histone post-translational modifications hPTMs within chromatin are epigenetic was unknown. To address this fundamental question, we devised a powerful, new method to temporally track in vivo the fate of parental nucleosomes during DNA replication at single gene resolution to rigorously assess nucleosome segregation as a function of the transcription status.
This procedure incorporated several stringent criteria to ensure that endogenous histones H3. Two female workers without wing are fighting for the queen throne with antennae twitching behavior.
Smaller ants with wings and lighter colors are male ants. Wandering behavior in the Orco mutant Wandering phenotypes displayed by Orco mutants. Summary What better way to probe changes in the epigenetic profile as a result of environmental cues than in a whole organism? In actuality, there is not much known about epigenetic changes that may underlie behavior. But which organism constitutes an experimentally-tenable resource of epigenetic processes?
It took a chance encounter with my scientific colleague and friend, Shelley Berger, to identify one. At a scientific meeting, Shelley mentioned her recent fascination with ant behavior after observing leaf cutter ants in Costa Rica. She suggested that ants might be a perfect organism to address the big question of an epigenetic basis underlying behavior.
Epigenetics includes chromatin constituents that impact directly or indirectly the chromatin structure and thus, the transcription status of genes. Importantly, these constituents are independent of the DNA sequence and yet, are also inherited during cell division.
Epigenetic changes foster specific gene expression profiles during development and must be maintained to safeguard cellular identity. Ants seemed to present an incredibly exciting, yet challenging opportunity to develop a model system-exciting because members of an ant colony exhibit well-defined behavioral and morphological differences that might arise from epigenetic phenomena, and challenging as we would need to develop genetics in ants to fully explore the processes involved.
In an invigorating collaborative effort funded by the Howard Hughes Medical Institute, we set out to establish ants as a model system to explore the epigenetic input underlying differences in longevity, social behavior and aging among the queen and other castes of an ant colony. Shelley and I brought several top-notch scientists of different expertise onboard.
For example, Juergen Liebig at Arizona State University is one of the top experts in studying how division of labor is maintained in insect societies.
For years, Juergen had been planning to expand his research to study differential gene expression underlying ant behavior and the differences in aging in his established model ant systems.
From Juergen, Shelley and I learned that ants exhibit a range of interesting behaviors, including high sociability and well-defined division of labor within their colonies. For example, the ants within a colony can assume either reproductive or non-reproductive roles.
In contrast, non-reproductive nestmates maintain the colony, raise the brood and forage for food, requiring complex brain function and hence a larger brain. The different reproductive roles also have a strong impact on the longevity of a queen and workers: a queen lives up to 10 times longer than worker ants. Even though these two types of ants have a high degree of genetic relatedness and begin life similarly, their individual experiences sculpt their brains and behaviors in vastly different ways.
One of the first goals of this extensive collaborative program was to fully sequence, assemble and begin annotating the genomes of two ant species: Camponotus floridanus Cflo and Harpegnathos saltatory Hsal , which we successfully achieved.
Some of our subsequent studies regarding the epigenetic basis of reproduction and aging in Hsal are described in Current Research, above. Because we succeeded in establishing genetics in Hsal using CRISPR technology, we can now fully study the function of genes involved in the processes described here and in Current Research and their effect on the epigenetic program-the overarching goal of this intensive endeavor.
EPIGENETICS DANNY REINBERG PDF
The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Epigenetics is a dynamic and well-established branch of genetics. It deals with heritable traits, which are not transmitted by the sequence of DNA but rather by the state of chromatin. The evolving landscape of epigenetic research has been reviewed in many excellent books and monographs. Built upon the foundation of the first edition published in , this new edition continues to deliver a solid basic knowledge of various epigenetic processes in model organisms including yeasts, ciliates, plants, insects, and mammals , of gene imprinting, of dosage compensation, of DNA methylation, and histone modifications. Twelve new chapters track the recent developments in epigenetic processes in cancer, neuronal development, and mental illness, in responses to the environment and in long-range chromatin interactions.
Danny Reinberg, PhD
Badal Gene expression — the process that cells use to produce proteins from genes on DNA strands — is fundamental to all life. Programs Programs HHMI empowers exceptional scientists and students to pursue fundamental questions in basic science. An invaluable resource for people going into the field of epigenetics. A Forceful Presence That aggressive curiosity also makes Reinberg a lively addition to any conference. Amazon Restaurants Food delivery from local restaurants.
Book review: Epigenetics (second edition, eds. Allis, Caparros, Jenuwein, Reinberg)
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