TY - JOUR
T1 - Epigenetic principles and mechanisms underlying nervous system functions in health and disease
AU - Mehler, Mark F.
N1 - Funding Information:
I am grateful to Solen Gokhan and Irfan Qureshi for critical reading of the manuscript and for inspired research initiatives and to John S. Mattick and members of his laboratory group for creative collaborations, for the development of innovative conceptual frameworks in the field of epigenetics and epigenomic medicine and for sharing of scientific information prior to publication. I regret that space constraints have prevented the citation of many important primary and secondary source materials. Supported by grants from the NINDS, NIMH, and NICHD, National Institutes of Health and from the Roslyn and Leslie Goldstein, the Mildred and Bernard H. Kayden, the F.M. Kirby, the Alpern Family and the Rosanne H. Silberman Foundations.
PY - 2008/12/11
Y1 - 2008/12/11
N2 - Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.
AB - Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.
KW - Cerebrovascular disorders
KW - Chromatin remodeling
KW - Environmental epigenomics
KW - Epigenetics
KW - Learning and memory
KW - Neurodegenerative diseases
KW - Neurodevelopmental disorders
KW - Neuroimmunology
KW - Neurooncology
KW - Neuropsychiatric diseases
KW - Non-coding RNAs
KW - Nuclear architecture
KW - Pharmacoepigenomics
KW - RNA and DNA editing
KW - RNA regulatory networks
KW - Stem cell biology
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U2 - 10.1016/j.pneurobio.2008.10.001
DO - 10.1016/j.pneurobio.2008.10.001
M3 - Review article
C2 - 18940229
AN - SCOPUS:57049151436
SN - 0301-0082
VL - 86
SP - 305
EP - 341
JO - Progress in Neurobiology
JF - Progress in Neurobiology
IS - 4
ER -