Chromatin accessibility dynamics during cell fate reprogramming

Abstract

Genome architecture and chromatin dynamics govern the fate and identify of a cell. Recent advances in mapping chromatin landscapes offer valuable tools for the acquisition of accurate information regarding chromatin dynamics. Here we discuss recent findings linking chromatin dynamics to cell fate control. Specifically, chromatin undergoes a binary off/on switch during iPSC reprogramming, closing and opening loci occupied by somatic and pluripotency transcription factors, respectively. This logic of a binary off/on switch may also be operational in cell fate control during normal development and implies that further approaches could potentially be developed to direct cell fate changes both in vitro and in vivo.

Keywords: chromatin dynamics; reprogramming; stem cell.

Figure 1. Hypothetic model of OSK binding to somatic and pluripotent enhancers

Three main approaches for reprogramming are shown on the left. The stages of reprogramming are shown in the middle. Reprogramming kinetics are shown on the right. Upon entry into somatic cells, OSK find ESC‐specific pluripotent enhancers (left arrow “high efficiency path”) or both somatic and pluripotent enhancers (right arrow “low efficiency path”), resulting in differences in reprogramming efficiencies.

Figure 2. Epigenetic modification is coupled with chromatin accessibility dynamics during reprogramming

During reprogramming, silenced ESC‐specific enhancers are activated by two steps, first by demethylation of H3K9me3/H3K27me3/5mC to remove epigenetic barriers; second by opening ESC‐specific enhancers and acetylation of the reprogrammed chromatin to keep it active.

Figure 3. Interfaces between pluripotent and somatic cell states

In each cell type, there are transcription factors, chromatin remodeling factors and epigenetic modifying enzymes that maintain a specific cell identity and resist reprogramming unless a specific group of genes is activated to alter cell fate.

Figure 4. TFs and epigenetic modifiers drive chromatin dynamics

During reprogramming, OSK first bind to closed ES‐specific enhancers and induce chromatin opening (close to open, CO) to activate epigenetic modifiers such as Sap30, which promote the shutdown of the open chromatin (open to close, OC) bound by somatic factors. Thus, CO/OC dynamics control the reprogramming path until full iPSCs formation.