Danny Reinberg, PhD. Terry and Mel Karmazin Professor of Biochemistry and Molecular Pharmacology, Department of Biochemistry and Molecular. Fax: () E-mail: [email protected] Lab website: Keywords: Epigenetics, Transcription, RNA Polymerase II, Histones, Non-coding RNA. Jan 1, Danny Reinberg has broken down everything from transcription up and criticized his colleagues for using the term “epigenetics” too loosely.
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HHMI is a science philanthropy whose mission is to advance basic biomedical research and science education for the benefit of humanity. HHMI empowers exceptional scientists and students to pursue fundamental questions in basic science.
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.
Danny Reinberg, PhD
These processes give rise to the distinctive patterns of proteins produced and the distinguishing traits and functions of the various tissues. Sanny 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. Our strategy involves intensive mechanistic analyses performed in vitro and with this information, exploring the integration and functioning of these mechanisms in vivo.
Our findings have been invigorating and gratifying, at times redirecting us towards unexpected, new areas of research. Polycomb Group PcG of Epigenetic Regulators The expression or repression of genes at epigeneticz transcriptional level boils down to the structural state of chromatin and whether it is made accessible or inaccessible to the transcriptional machinery. ESC exhibit their pluripotency through the repression of master regulatory genes.
These genes encode functions that when expressed, ultimately give rise to a committed cell lineage. We, and others have found that the Polycomb group PcG of proteins is key to maintaining the master regulator genes in a repressed state in ESC by directly impacting the chromatin state. When ESC differentiate, PcG proteins are removed from some of these master regulator genes dependent upon the particular cell lineage evolving.
Importantly, PcG proteins retain repression of those master regulatory genes whose expression is contraindicated to a particular lineage. Recruitment to Chromatin An open question in the field is exactly how PcG proteins latch onto their target genes in the first place.
PRC2 recruitment appears to be multi-faceted. In some cases, PRC2 interaction with long non-coding RNAs appears to be important, and this feature is an active line of study in my laboratory.
Signal transduction pathways also impact PRC2 recruitment. Erk binding directly promotes the formation of novel chromatin features associated with pluripotency, including PRC2 recruitment. Patterning and Inheriting Chromatin Domains Some promoter regions of master regulatory genes in ESC contain bivalent domains comprising both the repressive H3K27me3 modification catalyzed by PRC2 and the H3K4me3 modification associated with active transcription.
This ambivalence is generally envisioned as a flexible platform from which complete repression or activation of transcription resolves, dependent upon the developmental pathway. By canvassing cellular mononucleosomes, we assessed the natural occurrence of histone modifications: Surprisingly, both asymmetrical and symmetrical versions of modified nucleosomes were represented in the case of H3K27me3 and other modifications from ESC, fibroblasts, and cancer cells.
Whether H3K27me3 and H3K4me3 comprising the bivalent domain signature occur on separate but nearby nucleosomes, or on the same nucleosome was also settled. Both modifications reside within a single nucleosome, but only asymmetrically.
The biological rationale for this asymmetry became evident when we found that PRC2 is incapable of catalyzing H3K27me3 when H3K4me3 canny on both of the sister H3 histone tails. These findings set the stage for an elaborate investigation of how histone modifications are patterned to generate the resultant transcriptional programs.
A Biochemist by Nature | The Scientist Magazine®
These patterns are accurately propagated to daughter cells upon cell division. To tackle how such chromatin states are accurately propagated, we must learn precisely eeinberg nucleosomes and thus, their histone modifications, segregate during DNA replication. We are currently investigating this still uncharacterized process that is key to understanding inheritance of the proper transcriptional profile. A prime example of how unexpected findings can be especially gratifying, guiding us into an unexpected territory, involves our biochemical studies of the other mammalian Polycomb Repressive Complex, PRC1.
PRC1 actually exists in six major species, having common and exclusive proteins. Thus, the natural incorporation of the hitherto uncharacterized AUTS2 into a PRC1 complex has profound affects on the outcome to gene expression.
Epigenetics in a Model Organism To fully grasp the epigenetic basis of gene programming in the context of a whole organism, we are exploring the blueprinting of epigenetic features in experimentally approachable, social creatures: Having sequenced the reinberf of two ant species, we are now tackling the alterations in epigenetic features that accompany changes in ant morphology and behavior with an eye towards clues to unraveling the epigenetic programming of human behavior and the aging process.
This research was supported in part by grants from the National Institute of General Medical Sciences.
Danny Reinberg, Ph.D. | The Helen L. and Martin S. Kimmel Center for Stem Cell Biology
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