Reprogramming: identifying the mechanisms that safeguard cell identity

Abstract

Development and homeostasis rely upon concerted regulatory pathways to establish the specialized cell types needed for tissue function. Once a cell type is specified, the processes that restrict and maintain cell fate are equally important in ensuring tissue integrity. Over the past decade, several approaches to experimentally reprogram cell fate have emerged. Importantly, efforts to improve and understand these approaches have uncovered novel molecular determinants that reinforce lineage commitment and help resist cell fate changes. In this Review, we summarize recent studies that have provided insights into the various chromatin factors, post-transcriptional processes and features of genomic organization that safeguard cell identity in the context of reprogramming to pluripotency. We also highlight how these factors function in other experimental, physiological and pathological cell fate transitions, including direct lineage conversion, pluripotency-to-totipotency reversion and cancer.

Keywords: Cell identity; Reprogramming; Safeguarding.

Fig. 1.

Developmental plasticity. During differentiation, plasticity progressively decreases as safeguarding mechanisms are established to restrict cell fate. These safeguards must be overcome during reprogramming. Many of the same mechanisms play important roles in alternative cell fate changes (e.g. during transdifferentiation) and in cancer (e.g. during cellular transformation). ESC, embryonic stem cell; iPSC, induced pluripotent stem cell.

Fig. 2.

Developmental stages and reprogramming. Different reprograming methods (shown in bold; dedifferentiation, transdifferentiation, reversion and reprogramming) are depicted together with the developmental stage (i.e. the in vivo or in vitro counterpart) that each culture represents.

Fig. 3.

Chromatin-based safeguarding of cell identity. Various chromatin factors and transposable elements regulate cell identity by controlling chromatin 3D structure, nucleosome occupancy, histone modifications and the expression of adjacent genes. Activating regulators are shown in green while repressive regulators are shown in red.

Fig. 4.

RNA-based safeguarding of cell identity. (A) m⁶A (red) destabilizes mRNAs encoding key developmental factors, thus influencing cell fate change. (B) Alternative polyadenylation safeguards cell identity by regulating the expression of key transcripts during reprogramming. Proximal polyadenylation leads to a shorter 3′ UTR and eliminates cis-regulatory sequences to increase protein level expression of the corresponding gene. (C) Alternative splicing generates proteomic diversity that subsequently influences cell fate change.