The Epigenetic Paradox of Pluripotent ES Cells

Abstract

The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting "epigenetic paradox": even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this "epigenetic paradox" may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells.

Mitotic bookmarking in development and stem cells

“…Dissecting the reciprocal or hierarchical dependencies between mitotic bookmarking factors, epigenetic marks and mitosis-specific activities, and how these influence the restoration of a transcriptionally competent chromatin template in interphase, represents a stimulating area of research that could expand our general understanding of the molecular basis of cell identity. For this, comparative studies of several developmental stages and systems displaying differential requirements for epigenetic gene regulation, such as early mouse development (Festuccia et al, 2016b), or of those displaying very different temporal scales with regard to cell cycle progression and lineage determination, such as the fast cell cycles of pre-gastrulation development in several species, might be necessary.…”

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

“…Moreover, the primacy of TF binding relative to changes in DNA methylation has also been proposed during the Esrrb‐induced reprogramming of EpiSCs to a naïve state (Adachi et al , 2018). The ability of ESC self‐renewal to withstand complete loss of the DNA methylation machinery, with cell lethality of DNMT triple‐knockout ESCs only becoming apparent during differentiation (Tsumura et al , 2006), suggests that the increase in DNA methylation levels in committed cells reflects a change in the mode of gene regulation, from a dynamic process chiefly directed by TFs in pluripotent cells to one stabilized by DNA methylation (Festuccia et al , 2017). …”

Basic Science Model of Blood as an Electron-Delivery Circuit Describes the Evolution of the Human Circulation

“…In embryogenesis and adult life, cell fate decision and maintenance is controlled by transcription factors and other redox signaling cues acting on the genome [49]. The role of the topologically-organised, redoxing haem circuit in vertebrate mitochondrial energy production and body-wide cellular expression deserves further investigation.…”