Emerging roles of the histone chaperone CAF-1 in cellular plasticity

Abstract

During embryonic development, cells become progressively restricted in their differentiation potential. This is thought to be regulated by dynamic changes in chromatin structure and associated modifications, which act together to stabilize distinct specialized cell lineages. Remarkably, differentiated cells can be experimentally reprogrammed to a stem cell-like state or to alternative lineages. Thus, cellular reprogramming provides a valuable platform to study the mechanisms that normally safeguard cell identity and uncover factors whose manipulation facilitates cell fate transitions. Recent work has identified the chromatin assembly factor complex CAF-1 as a potent barrier to cellular reprogramming. In addition, CAF-1 has been implicated in the reversion of pluripotent cells to a totipotent-like state and in various lineage conversion paradigms, suggesting that modulation of CAF-1 levels may endow cells with a developmentally more plastic state. Here, we review these exciting results, discuss potential mechanisms and speculate on the possibility of exploiting chromatin assembly pathways to manipulate cell identity.

Figure 1. Chromatin accessibility and modifications during development and nuclear reprogramming

Development is accompanied by a gradual increase in chromatin compaction and the acquisition of repressive histone and DNA methylation patterns, which stabilize somatic cell fate and function as barriers to cellular reprogramming. Reprogramming to pluripotency and totipotency reverses these processes by chromatin decompaction (red arrows) and loss of silencing marks. The overexpression of transcription factors in somatic cells yields induced pluripotent stem cells (iPSCs) while the injection of somatic nuclei into oocytes by somatic cell nuclear transfer (SCNT) yields totipotent cells. CAF-1 suppression enhances the reprogramming of somatic cells to iPSCs and of ESCs/iPSCs to a totipotent-like state.

Figure 2. Roles of CAF-1 in controlling cellular plasticity

CAF-1 suppression facilitates cell fate change in different cellular systems with or without ectopic expression of transcription factors. Most cell fate switches were performed ex vivo using mouse cells unless noted. MEF (Mouse Embryonic Fibroblast), HSPC (Hematopoetic Stem and Progenitor Cell)

Figure 3. Functional diversity of the CAF-1 complex and its influence on chromatin structure and histone modifications

Depiction of CAF-1 complex composition, highlighting its function as (1) a replication-dependent histone chaperone via its interaction with PCNA and association with H3/H4 histone tetramers, (2) heterochromatin silencing factor via recruitment of silencing complexes such as HP1/Sedtb1, which influence H3K9me3 deposition and LSD1 and HDAC, which influence erasure of H3K4 di- and tri-methylation and H3 acetylation.

Figure 4. Mechanisms by which suppression of CAF-1 facilitates acquisition of a pluripotent or totipotent-like state

Shown are models of how CAF-1 modulation may influence chromatin accessibility and histone modifications over distinct chromatin domains. During the reprogramming of somatic cells to iPSCs, suppression of CAF-1 acts locally at enhancer elements, making them more accessible to transcription factor binding. CAF-1 suppression also results in a local reduction of the H3K9me3 silencing mark at 2-cell (2C) stage-associated “reprogramming resistant regions” (RRRs), which are normally repressed in somatic cells. During the conversion of ESCs to a 2C-like state upon CAF-1 suppression, chromatin becomes more accessible globally, resulting in activation of endogenous retro-elements, such as MERVL transcripts, and neighboring genes.