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  • It has recently emerged that successive stages of early mamm

    2018-10-26

    It has recently emerged that successive stages of early mammalian development are linked with expression of distinct classes of transposable element (TE) (Goke et al., 2015). For example, MERVL elements and their cognate MT2 LTR become active specifically at the 2-cell (2C) stage in mice, while HERVK is active from the 8-cell stage in human embryos (Peaston et al., 2004; Grow et al., 2015). These elements can significantly influence expression of nearby genes. For example, TE can act as co-opted promoters that splice to downstream genes thereby generating “chimeric transcripts” (Macfarlan et al., 2012). In addition, TEs can affect gene expression through promoting open chromatin configurations, production of long noncoding RNAs (lncRNA), or by acting as enhancers (Thompson et al., 2016). The impact of TEs may be particularly prevalent in pluripotent cells, since TEs are under selective pressure to be active in pluripotent or germline phases in order to propagate transgenerationally (Bourque et al., 2008). Indeed, HERVH elements have a key role in contributing to the pluripotency network in hESCs (Wang et al., 2014). Thus, TEs represent a relatively unexplored regulatory source for the establishment and control of alternate pluripotent states. Here, we identify a spectrum of ESC states and characterize the distinct transcriptional networks and epigenome at each node. Distinct classes of TEs are active between pluripotent conformations and influence the emergent transcriptome. Strikingly, some naive culture conditions license dynamic activation of master regulators for a specific primary germ layer (endoderm or ectoderm) or primordial germ bet bromodomain (PGCs). Mechanistically, we identify Klf4 and LIF/STAT3 as the key regulators of a Blimp1 PGC-like ESC state. Overall we report that ESC populations can occupy a continuum of transcriptional states, in part through accessing sub-states under certain culture parameters.
    Results
    Discussion Our study reports a spectrum of distinct transcriptional states of pluripotency that appear to order from most naive associated to most developmentally advanced. The spectrum reflects a response to culture conditions, which influence the overall ESC transcriptome and epigenome, as well as controlling access to sub-populations. The continuum of ESC states is coupled with a gradient of increasing global DNA methylation levels, with the more hypomethylated states most closely linked with a naive signature. Moreover, alternate pluripotent conformations are linked with activation of at least some distinct classes of TEs. This, in turn, appears to influence the transcriptome, potentially through a number of routes, such as opening local chromatin structure, acting as enhancers, or forming chimeric transcripts (Chuong et al., 2016). We observed that the latter mechanism is prevalent, with chimeric transcript expression often being restricted to a unique or subsets of pluripotent conditions. Stage-specific activation of TEs has been observed during early embryonic development, and is thought to have been co-opted to drive gene regulatory networks in a stepwise manner (Thompson et al., 2016). In this way, sequential TE activation may coordinately regulate groups of genes required for successive stages of ontogeny. An example of this can be seen at the 2C embryonic stage, where multiple key genes are activated as chimeric transcripts from MT2 and MERVL elements (Macfarlan et al., 2012). The observation that the distinct ESC conformations observed here are also linked with differential TE activity suggests that TEs may contribute to overall pluripotent status. Notably it is possible that the gradient of epigenomic states across conditions partially underpins differential TE expression, as TEs are generally more prominently activated in hypomethylated ESCs here, and transition between pluripotent/epigenetic states is also linked with distinct TE responses (Walter et al., 2016). Moreover, repeat elements activated in the more derestricted epigenetic states along the spectrum, such as LTR45 and IAP, correlate well with TEs activated upon deletion of epigenetic regulators (Reichmann et al., 2012). This collectively implies a direct relationship between the epigenome, TE activity, and overall cell state.