No abstract

Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), especially on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their associated complexes, is predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here we summarize key features in molecular recognition of histone PTMs by a diverse family of 'reader pockets', highlighting specific readout mechanisms for individual marks, common themes and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biology and disease, notably cancer.The vast majority of DNA in eukaryotic organisms is intimately wrapped around core histone proteins, forming chromatin, the physiological context in which the genomes of these organisms must function. Control of the dynamics of chromatin structure has been implicated widely in regulating both access to and interpretation of the associated DNA template 1 . For example, numerous studies suggest that gene expression patterns can be positively or negatively regulated by complexes of proteins that fine-tune the structural properties of chromatin, often through covalent PTMs of histone proteins or other chromatin-remodeling complexes 2,3 . As chromatin architecture may be transmissible to daughter cells along a particular developmental lineage, histones and their PTMs are likely candidates for epigenetic information carriers that propagate phenotypic determinants not encoded in the DNA sequence. More than 70 different sites for histone PTMs and eight HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript types of histone PTMs have been reported, largely from the extensive application of mass spectrometry-and antibody-based detection techniques, as well as from metabolic-labeling studies [1][2][3] . Remarkably, almost two-thirds of potentially modifiable residues on histones have been characterized as PTM sites, and as more sensitive detection methods become available, this number is likely to increase. Despite the large number of histone PTMs, only a subset of amino acid residues in histones are known to be covalently modified, which include lysine (K), arginine (R), serine (S), threonine (T), tyrosine (Y), histidine (H) and glutamic acid (E) 1 . The majority of the PTMs are additions of relatively small yet chemically and structurally distinct moieties, such as acetyl, methyl and phosphate groups (Fig. 1a); these have been identified on sites ranging from the flexible tail...

Nucleic acid molecules play crucial roles in diverse biological processes including the storage, transport, processing, and expression of the genetic information. Nucleic acid aptamers are selected in vitro from libraries containing random sequences of up to a few hundred nucleotides. Selection is based on the ability to bind ligand molecules with high affinity and specificity. Three-dimensional structures have been determined at high resolution for a number of aptamers in complex with their cognate ligands. Structures of aptamer complexes reveal the key molecular interactions conferring specificity to the aptamer-ligand association, including the precise stacking of flat moieties, specific hydrogen bonding, and molecular shape complementarity. These basic principles of discriminatory molecular interactions in aptamer complexes parallel recognition events central to many cellular processes involving nucleic acids.

DNA methylation occurs in CG and non-CG sequence contexts. Non-CG methylation is abundant in plants, and is mediated by CHROMOMETHYLASE (CMT) and DOMAINS REARRANGED METHYLTRANSFERASE (DRM) proteins; however its roles remain poorly understood. Here we characterize the roles of non-CG methylation in Arabidopsis thaliana. We show that a poorly characterized methyltransferase, CMT2, is a functional methyltransferase in vitro and in vivo. CMT2 preferentially binds histone H3 lysine 9 (H3K9) dimethylation and methylates non-CG cytosines that are regulated by H3K9 methylation. We revealed the contributions and redundancies between each non-CG methyltransferase in DNA methylation patterning and in regulating transcription. We also demonstrate extensive dependencies of small RNA accumulation and H3K9 methylation patterning on non-CG methylation, suggesting self-reinforcing mechanisms between these epigenetic factors. The results suggest that non-CG methylation patterns are critical in shaping the histone modification and small non-coding RNA landscapes.