NuRD and pluripotency: a complex balancing act

Abstract

Embryonic stem cells (ESCs) are defined by two essential features--pluripotency and self-renewal--whose balance requires the concerted action of signal transduction pathways, transcription factor networks, and epigenetic regulators. Recent findings have implicated the NuRD chromatin remodeling complex in the sophisticated choreography of ESC regulatory pathways.

Figure 1. NuRD complex opposes histone acetyltransferases in dynamic regulation of the ESC transcriptional program

A. A dynamic model for NuRD complex function based on the work from Hendrich and colleagues (Reynolds, 2012a; Reynolds et al., 2012b). At genes integral to the pluripotency program, histone acetyltransferase (HAT) enzymes function as chromatin regulators promoting gene activity. NuRD complex, through its histone deacetylase subunits (HDAC), opposes their function and serves to dampen expression. Balance between the activating functions of HAT enzymes and the repressive HDAC activity of NuRD fine tunes expression of these genes. At bivalent genes that are poised for activation during embryonic development, the HDAC functions of NuRD are required for stable association of PRC2, and maintenance of H3K27me3. B. In the work of (Whyte et al. (2012), NuRD complex HDAC activity acts in competition with p300 or other HAT enzymes at active enhancers in pluripotent cells to maintain a balance of histone acetylation under normal ESC growth conditions. Under conditions favoring differentiation, NuRD deacetylates histone H3K9, making this histone a substrate for LSD1 to demethylate H3K4, a necessary step in turning off an enhancer occupied by the core pluripotency network. Loss of enhancer activity results in downregulation of transcription and, ultimately, in gene silencing. C. Yildrim et al. (2011) depict NuRD complex in competition with the esBAF complex at highly transcribed genes, including genes downstream of LIF-Stat signaling. These two chromatin regulators act in an opposing fashion to regulate nucleosome occupancy through the ATPase subunits BRG1 (esBAF) and Mi-2β (NuRD). The balance of these activities at core promoters serves to fine tune RNA polymerase recruitment.

Figure 2. NuRD complex action and distribution in the ESC genome

A. Fazzio and colleagues provide evidence suggesting that NuRD complex localizes to specific regions of the genome through direct interaction of MBD3 with 5hmC modified DNA, a mark deposited by TET1. B. ChIP PCR (Reynolds et al., 2012a) and ChIP-Seq (Reynolds et al., 2012b) depict (yellow shaded areas) broad distribution of NuRD complex across kilobases of DNA surrounding the TSS of pluripotency genes. Note that this model depicts a gap in NuRD complex enrichment over the TSS. ChIP-Seq (Yildrim et al., 2011) determination of focal localization of NuRD complex in ESCs (yellow shaded areas). Strongest peaks were detected slightly downstream of the TSS, little to no enrichment was noted at enhancers. ChIP-Seq (Whyte et al., 2012) of NuRD complex in ESCs (yellow shaded areas) in focal areas of enrichment coincident with both enhancers and core promoters. Enrichment at enhancers was noted in peaks larger than those detected near the TSS.