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Proteostasis of hESC Report Summary

Project ID: 630654
Funded under: FP7-PEOPLE
Country: Germany

Periodic Report Summary 1 - PROTEOSTASIS OF HESC (Proteostasis of aging and stem cells)

With age, post-mitotic cells lose extensive control of the proteostasis equilibrium: wide spread, aberrant changes in translation, a loss of function in protein degradation machineries, and a generalized down regulation of chaperones often appear in differentiated cells across time. This demise in protein homeostasis, or proteostasis, is considered one of the hallmarks of aging. Human embryonic stem cells (hESC) demonstrate a striking capacity to avoid senescence – a capacity that necessarily demands avoidance of any imbalance in proteostasis that would otherwise compromise their function during replication. Thus, we hypothesize that hESCs can provide a novel paradigm to study proteostasis and its demise during the aging process. For this purpose, our aim is to define the regulation of proteostasis in hESCs and how this network impinges upon hESC function. In addition, we seek to determine how these proteostasis mechanisms can be adapted to alleviate age-related pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). For this purpose, we use an innovative approach based on a combination of hESCs research with genetic analysis in C. elegans. In our previous work, we discovered that hESCs exhibit high proteasome activity compared to their differentiated counterparts. Furthermore, we uncovered that PSMD11/rpn-6, a key proteasomal subunit, is required for this increased proteasome activity. Interestingly, ectopic expression of RPN-6 in somatic tissues is sufficient to induce proteotoxic resistance and extend healtshpan in the organismal model C. elegans. However, the mechanisms by which the ubiquitin proteasome system regulates hESC function and aging remain unknown. Besides the ubiquitin proteasome system, we hypothesize that other proteostasis mechanisms are also increased in hESCs. In this project, we performed quantitative proteomics to define increased components of the ubiquitin proteasome system and other proteostasis nodes in hESCs compared with their differentiated counterparts. Notably, we found that hESCs exhibit profound differences in the levels of a significant number of proteostasis regulators. This systematic analysis of the proteostasis network was critical to establish our laboratory and future research lines. Here, in particular, we focused on E2 enzymes, the main determinants for selection of the lysine to construct ubiquitin chains, which thereby directly control the cellular fate of the substrate. Interestingly, we found an increase in three E2 enzymes in hESCs. Thus, we examined whether these increased E2 enzymes impinge upon hESC function. We observed that one of these E2 enzymes is required for neuronal differentiation of hESCs. Moreover, this E2 enzyme bound to specific H3 histones and its loss induced an increase in H3K9me3, a repressive transcriptional mark. Notably, changes in histone methylation induced by modulation of our target E2 hasten the aging process in C. elegans. Taken together, our results indicate a novel connection between E2 enzymes, histone modification, hESC identity and organismal aging. During the next two years, we will seek to understand the molecular mechanisms by which our target E2 modulates histone methylation and how this regulatory pathway affects cell fate decisions and aging. Our research can address two important challenges: 1) defining hESC identity and neurogenesis as well as 2) determining regulators of the aging process that might, in turn, protect from the symptoms associated to human age-related diseases.

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Life Sciences
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