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  • br Management of Hypertension The aim of treating

    2019-10-09


    Management of Hypertension The aim of treating HT is to reduce the risk of adverse cardiovascular outcomes: mainly coronary artery disease, stroke, and death. For this reason, the decision whether to initiate pharmacological treatment or not will depend not only on BP values, but also on the overall cardiovascular (CV) risk. Different calculators are available to estimate the individual CV risk in patients without established cardiovascular disease. The ESC/ESH guidelines support the use of the SCORE calculator (an estimation of the 10-year risk of a first fatal atherosclerotic event), and American guidelines recommend the ACC/AHA Pooled Cohort Equation (that calculates the 10-year risk of atherosclerotic cardiovascular disease). It is important to know that these calculators have been developed for specific populations, and their use in non-tested subgroups should be discouraged.
    Conclusions and Take-Home Messages
    Introduction Only about 1.5% of mammalian genomes are comprised of single-copy protein-coding sequences, whereas approximately half of their DNA derives from transposable elements (TEs). Despite their abundance, the roles and regulation of TEs have been understudied, in large part because of the difficulty in mapping repetitive sequences to the genome. Nevertheless, TEs are now accepted as key drivers of genome evolution by rewiring gene regulatory networks, including in the human genome (Bourque, 2009). The retrotransposon long interspersed element 1 (LINE1) makes up the largest proportion of TE-derived sequences, and is the only class of autonomous TEs still active in human (Magiorkinis et al., 2015). LINE1-induced mutations have been linked to a growing number of diseases, including hematopoietic and neurological disorders as well as several types of cancer (reviewed in Burns [2017]). For this reason, LINE1 is generally thought to be silenced in differentiated cell types to avoid uncontrolled mutagenesis. However, the view of TEs such as LINE1 as strictly detrimental to AT7519 Hydrochloride kinase may be too simplistic. LINE1 is expressed in normal neural progenitor cells, where it has been proposed to promote neuronal diversity (Muotri et al., 2005). LINE1 is also expressed in the pre-implantation embryo (Fadloun et al., 2013) and in the fetal germline (Ohno et al., 2013, Percharde et al., 2017b). A TE of a different class, mouse endogenous retrovirus type L (MERVL), is also expressed in cleavage-stage embryos, where it drives the expression of many transcripts specific to zygotic genome activation (ZGA) and totipotency (Kigami et al., 2003, Macfarlan et al., 2012, Svoboda et al., 2004). Importantly, the rate of LINE1 retrotransposition in embryos and germ cells in vivo is low given the high levels of LINE1 RNA expression (Kano et al., 2009, Richardson et al., 2017, Newkirk et al., 2017). These observations raise the possibility that LINE1 RNA has as of yet undefined cellular roles, independent of retrotransposition.
    Results
    Discussion The expression of TEs such as LINE1 is generally thought to be detrimental to cells because it can cause mutations or apoptosis (e.g., Malki et al., 2014, Burns, 2017). In contrast, we report here that the expression of LINE1 regulates exit from the 2-cell state by performing two main functions: repressing the 2C program induced by Dux, and activating rRNA synthesis to support rapid proliferation. These two functions are unified by the interaction of LINE1 RNA with Nucleolin, which we identify as a novel repressor of the Dux/2C program. Thus, rather than being a simple genomic parasite, LINE1 may be best viewed as a symbiont that is an integral part of the transcriptional networks that regulate cellular potency during early mammalian development (Figure 7L). Nucleolin is most commonly associated with the positive regulation of rRNA synthesis (Ginisty et al., 1998). In recent years, Nucleolin has been shown to also have roles in chromatin remodeling, DNA replication, and DNA repair (reviewed in Jia et al. [2017]). Our work uncovers a novel function for Nucleolin, and it will be of interest to identify the functional elements in the LINE1 RNA by defining the regions that interact with Nucleolin and potentially other factors, like Kap1. Intriguingly, the region of mouse LINE1 RNA previously used to identify Nucleolin as an interactor was the inter-ORF (Peddigari et al., 2013), the same region against which we designed the LINE1 ASO (Figure 1C). It is therefore possible that the ASO disrupts the interaction between LINE1 RNA and Nucleolin, which in turn may contribute to destabilizing LINE1 RNA.