Chromatin dynamics during cellular reprogramming

Abstract

Induced pluripotency is a powerful tool to derive patient-specific stem cells. In addition, it provides a unique assay to study the interplay between transcription factors and chromatin structure. Here, we review the latest insights into chromatin dynamics that are inherent to induced pluripotency. Moreover, we compare and contrast these events with other physiological and pathological processes that involve changes in chromatin and cell state, including germ cell maturation and tumorigenesis. We propose that an integrated view of these seemingly diverse processes could provide mechanistic insights into cell fate transitions in general and might lead to new approaches in regenerative medicine and cancer treatment.

Figure 1. Dynamics of key epigenetic and transcriptional changes during direct reprogramming

Colored bars represent different cellular and transcriptional events (top panel) or epigenetic modifications (bottom panel) that change in dynamic patterns during iPSC formation. Examples of candidate enzymes that have been associated with these epigenetic marks in the context of direct reprogramming are given on the right. OKSM: Oct4, Klf4, Sox2, cMyc; 5mC: 5′-methyl-Cytosine; 5hmC: 5′-hydroxy-methyl-Cytosine; MET: Mesenchymal-to-epithelial-transition.

Figure 2. Interplay between reprogramming factors and molecules influencing chromatin state

Shown are different transcription factors that have been shown to trigger induced pluripotency, with the classical combination (Oct4, Sox2, Klf4, c-Myc) highlighted. Below each category are examples of molecules that have been shown to facilitate (green) or inhibit (red) reprogramming. BMPs (Bone Morphogenetic Factors) and Wnts have stage-dependent enhancing or suppressive roles during iPSC formation (black, see text for details). RBPs: RNA Binding Proteins.

Figure 3. Levels of epigenetic gene regulation during induced pluripotency

a. Depicted are four categories of genes with associated histone modifications and their transcriptional response during reprogramming. Examples of genes within each category are shown to the right. b. Gain and loss of DNA methylation occurs late in reprogramming, while the acquisition of hydroxymethylation at pluripotency genes takes place at early-to-mid stages of iPSC formation. c. Oct4 (O), Klf4 (K) and Sox2 (S) function as “pioneer factors” that bind to high-density nucleosome regions, enabling chromatin remodeling and the recruitment of other factors including c-Myc (M). d. Changes in long-range chromatin interactions around the Nanog locus during iPSC formation. iPSC formation re-establishes a 3D chromatin network typical of ESCs, and this process depends on Mediator and Cohesin. Colored loops represent somatic-specific (orange), intermediate-specific (green) and pluripotency-specific (blue) Nanog-interacting loci.