However, whether the cationic component of the interaction is necessary for binding in the aromatic cage has not been addressed. In this article, the interaction of trimethyllysine with tryptophan is compared with that of its neutral analog, tert-butylnorleucine (2-amino-7,7-dimethyloctanoic acid), within the context of a ␤-hairpin peptide model system. These two side chains have near-identical size, shape, and polarizabilities but differ in their charges. Comparison of the two peptides reveals that the neutral side chain has no preference for interacting with tryptophan, unlike trimethyllysine, which interacts strongly in a defined geometry. In vitro binding studies of the histone 3A peptide containing trimethyllysine or tert-butylnorleucine to HP1 chromodomain indicate that the cationic moiety is critical for binding in the aromatic cage. This difference in binding affinities demonstrates the necessity of the cation-interaction to binding with the chromodomain and its role in providing specificity. This article presents an excellent example of synergy between model systems and in vitro studies that allows for the investigation of the key forces that control biomolecular recognition.cation-pi interactions ͉ histone code ͉ lysine methylation ͉ posttranslational modifications ͉ protein-protein interactions W ith rapid advancements in genomics, epigenetics has become the next major challenge in understanding how genetic information is controlled (1). It is becoming clear that posttranslational modifications of proteins are a key component in controlling gene expression. These modifications include a number of subtle structural changes, including Lys and Arg methylation, Lys acylation, and Ser/Thr/Tyr phosphorylation, which act as chemical switches to induce or repress proteinprotein interactions. Among all histone modifications, lysine methylation is especially important for chromatin function because of its stability and direct contribution to heritable patterns of gene expression (for review, see ref.2). To understand how such modest structural modifications can control biomolecular recognition events, it is critical to understand the underlying noncovalent interactions involved.Methylation of Lys induces a protein-protein interaction through the binding of methyl lysine (KMe n , n ϭ 1-3) in an aromatic cage. This interaction first was described for the binding of methylated histone 3 (H3) tail to the HP1 chromodomain ( Fig. 1) (3, 4). HP1 and methylated H3 interact specifically whether lysine 9 is mono-, di-, or trimethylated. However, the binding is most effective when lysine is trimethylated (5). In addition, more recent findings have shown that phosphorylation of serine 10 prevents interaction of HP1 with methylated H3 (for review, see ref. 6). Therefore, a binary switch mechanism has been proposed for the recognition of methyllysine-containing peptides by chromodomains. Interestingly, binding of a methylated lysine in an aromatic cage is not exclusive to chromodomains. Plant homeobox domain (PHD) fingers an...

The chromatin organization modifier domain (chromodomain) was first identified as a motif associated with chromatin silencing in Drosophila. There is growing evidence that chromodomains are evolutionary conserved across different eukaryotic species to control diverse aspects of epigenetic regulation. Although originally reported as histone H3 methyllysine readers, the chromodomain functions have now expanded to recognition of other histone and non-histone partners as well as interaction with nucleic acids. Chromodomain binding to a diverse group of targets is mediated by a conserved substructure called the chromobox homology region. This motif can be used to predict methyllysine binding and distinguish chromodomains from related Tudor “Royal” family members. In this review, we discuss and classify various chromodomains according to their context, structure and the mechanism of target recognition.

The ubiquitin-proteasome system (UPS) plays an integral role in controlling protein turnover to modulate cellular processes such as growth, proliferation, differentiation, and apoptosis. This occurs through multiple mechanisms that rely on the regulation of numerous transcription factors such as steroid hormone nuclear receptors. The glucocorticoid receptor (GR) is a member of this receptor family and its activation promotes nuclear translocation and downstream transcriptional activity through the recruitment of co-regulatory complexes. Our goal is to understand the mechanisms by which the proteasome regulates glucocorticoid receptor-mediated gene transcription. To explore the effects of proteasome inhibition upon GR-mediated transcription, we used ChIP-Seq and microarray studies using breast cancer cells to examine GR binding and gene expression profiles after treatment with dexamethasone (dex) or dex in combination with a proteasome inhibitor, MG132 (dex + mg), for 1 hour and 18 hours. More than 14000 and 5000 GR-binding sites were apparent after both treatments in the 1 hour and 18 hour samples, respectively. GR binding sites seen during 1 hour of treatment can be mapped to more than 9000 genes while the binding sites in the 18 hour treatment samples mapped to over 5000 genes. In addition, over 55% of binding sites in all treatment groups are within 50 kilobases of annotated transcription start sites. To verify these putative interactions, we assayed the transcript levels of genes at both time periods and examined the levels of bound GR throughout the gene. The results reveal a differential regulation of genes that can be divided into three classes: dex-responsive, dex + mg-responsive, or dually responsive. Further analyses will reveal if there are clearly defined chromatin states that demarcate each class. These data provide insights into the intricate mechanisms of proteasome-mediated GR regulation and highlight proteasomal-regulated genes involved in numerous diseases and developmental disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3928. doi:1538-7445.AM2012-3928

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Objectives: Many behavioral health providers (BHPs) in primary care practices spend a majority of their time addressing mental health rather than behavior change. We wanted to better understand the practice of BHPs in integrated primary care. Methods: Survey of BHPs from practices participating in the Colorado State Innovation Model (SIM) initiative. The survey measured what diagnoses BHPs receive referrals to treat, what they treat regardless of referral reason, which techniques they use, and think are most effective for mental health diagnoses and behavior change/weight management support, and their interest in providing support for weight management. Results were analyzed using descriptive statistics and Spearman correlations. Results: We received 79 surveys representing 64 out of 248 SIM practices (practice response rate of 26%). BHPs reported addressing health-related behaviors with patients referred to them for mental health diagnoses. They expressed interest in health behavior and believed the techniques they use for traditional mental health diagnoses also support behavior change. Most reported using cognitive behavioral therapy (89%), mindfulness (94%), and relaxation/stress management (94%). Time in practice was associated with receiving more referrals for weight management (rho(76) = .271, P = .018) and with addressing diet (rho(75) = .339, P = .003) and weight management (rho(75) = .323, P = .005). BHPs in practices that had care managers were more likely to report receiving referrals for weight management than BHPs in practices that did not employ a case manager ([Formula: see text](76) = .222, P = .038); practices employing a health coach were more likely to receive referrals for physical activity than practices without a health coach ([Formula: see text](76) = .257, P = .015). Conclusions: BHPs are interested in and frequently address health related behavior. Formalizing health behavior services from BHPs in primary care may provide opportunities to better support patients with behavior change and subsequently improve health outcomes.