DNA and its associated histones are the two main components of chromatin and together they organize the genetic information within the cell and serve as a backdrop for a vast array of essential cell biology including DNA replication, transcription, recombination and repair. However chromatin is not static, it is altered by the addition of various chemical tags, termed chromatin modifications, to DNA and/or histones. One such modification, DNA methylation, is associated with gene silencing and plays important roles in diverse biological processes including imprinting, cellular differentiation and the maintenance of genome integrity. Yet, our understanding of how specific DNA methylation patterns are established and how they lead to gene silencing is poorly understood. Gaining insight into these facets of DNA methylation will be critical not only in understanding normal processes but also in understanding how alterations in methylation patterns can lead to developmental defects and the progression of diseases. This proposal focuses on understanding the roles of several newly identified protein complexes in the plant model Arabidopsis thaliana. These complexes are proposed to play key roles in facilitating gene silencing by modulating chromatin structure and in establishing locus- and/or cell type-specific patterns of DNA methylation. The goals of these studies are to mechanistically connect DNA methylation to changes in chromatin that are refractory to gene expression and to assign specific components of the DNA methylation machinery to unique DNA methylation patterns. Together, these findings will expand our knowledge of how DNA methylation, gene silencing, and developmental programs are coupled-a critical process for normal growth and development that when disrupted contributes both acute and chronic diseases. Arabidopsis is an ideal system to study epigenetic processes, like DNA methylation, as it is genetically malleable, has a small genome that is highly amenable to genome-wide analyses, and is tolerant of dramatic changes in its epigenetic landscape. In addition, many of the key players and pathways involved in establishing and maintaining epigenetic modifications are conserved between plants and mammals. Thus, understanding of the machinery that shapes DNA methylation profiles and in turn, understanding of how DNA methylation influences downstream processes like transcription in plants, will be applicable to analogous processes in mammals.

Public Health Relevance

One major aspect controlling gene expression in eukaryotes involves the addition of specific chemical groups, termed epigenetic modifications, to DNA and histones-two major components of chromatin. These modifications influence the expression of the underlying genes and play critical roles in diverse biological processes including imprinting, development, and gene silencing. To investigate how epigenetic modifications control gene expression, which will be critical not only in understanding normal processes but also in understanding how alterations in the epigenetic landscape can lead to developmental defects and the progression of disease states, this proposal focuses on characterizing the roles of several newly identified protein complexes that modulate DNA methylation patterns in the plant model organism Arabidopsis thaliana.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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Salk Institute for Biological Studies
La Jolla
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Zhou, Ming; Palanca, Ana Marie S; Law, Julie A (2018) Locus-specific control of the de novo DNA methylation pathway in Arabidopsis by the CLASSY family. Nat Genet 50:865-873
Li, Dongming; Palanca, Ana Marie S; Won, So Youn et al. (2017) The MBD7 complex promotes expression of methylated transgenes without significantly altering their methylation status. Elife 6:
Zhou, Ming; Law, Julie A (2015) RNA Pol IV and V in gene silencing: Rebel polymerases evolving away from Pol II's rules. Curr Opin Plant Biol 27:154-64