The core NuRD complex and its transcriptional factors which recruit the core NuRD complex to the promoter of the respective target genes.6

Interaction and regulation of the Mi-2/NuRD complex on Oct4. Mi-2/NuRD complexes could regulate the activity of Oct4 by mechanisms in transcription at multiple points. Points of regulation by different activities are shown by colored lines. Factors in green and blue (such as Oct4 itself) carry out positive regulatory activities, including H3K4 methylation; those in red act in a negative capacity (eg, DNA and H3K9 methylation). Protein-protein interactions between Mi-2/NuRD with others are shown with arrows or “rays” on a star. CR1–4 are Oct4 promoter and enhancer regions with conservation. Reprinted from Trends Biochem Sci, 2009;34, Kanga J, Shakyaa A, Tantina D., Stem Cells, Stress, Metabolism and Caner: A drama in two Octs, 1–9, copyright 2009, with permission from Elsevier.

The comprehensive biological and molecular view of the Mi-2/NuRD complexes and stemness, longevity/ageing, and cancer in adults in mammals and nematodes.

Hypothesized Mi-2/NuRD and DICER silencing. The Mi-2/NuRD complex is possibly enriched in the H3K9me3, heat shock factor-1, and heterochromatin protein-1 regions. RNA molecules are hypothesized to contribute to the structure of the CT and PCT regions. In human cells, all dsRNAs encoded by the PCT regions are hypothetically generated by inhibitory RNA machinery (Dicer, RITS, and RDRC). In humans, CT regions are made of a repetition of AT-rich alpha satellite motifs. The size and structure of the PCT regions are made up of satellite repeats. Such regions might be preferred by stemness factors. Adapted with permission from The International Journal of Developmental Biology (Int. J. Dev. Biol.) 2009;53:259–268.

Model of stress, the Mi-2/NuRD complex and repair of DNA damage. Upper: Ultraviolet light upregulates the level of Mi-2 protein.6 Bottom: Summary of the Mi-2/NuRD mechanism in the response to DNA damage. In response to DNA damage caused by ultraviolet light or ionizing radiation, the Mi-2/NuRD complex is rapidly recruited to the site of damaged DNA and exerts its function in DNA repair by many different mechanisms, including RNF168 level ubiquination, blocking the ongoing transcription, and so on. Adapted with permission from.103

Schematic representation of the role of the Mi-2/NuRD -p53-micro RNA network in induced pluripotent stem cells and cancer stem cells. Normal fibroblasts, which are mature, differentiated cells, can be reprogrammed into induced pluripotent stem cells or tumor cells by a combination of defined factors. Adapted by permission from Macmillan Publishers Ltd, Nature, 2009;460:1085–6, copyright 2009. Left: The transcription factors c-myc and Klf4 promote reprogramming of fibroblasts into induced pluripotent stem cells in a manner that conceptually parallels their roles in transforming normal cells into tumor cells. Oct4 and Sox2, although overexpressed in cancers, are currently thought to function specifically to promote formation of induced pluripotent stem cells. Right: The p53 tumor suppressor gene is a well known master regulator that helps downregulate the genes required for proliferation and survival. p53 directly or indirectly limits the reprogramming of fibroblasts into induced pluripotent stem cells or into transformed cancer cells by inducing apoptosis, or cellular senescence through its target protein, the cell-cycle inhibitor p21, which promotes arrested growth and cell death in response to various stress signals.

Model of soma-to-germline transformation in Caenorhabditis elegans and possible stochastic cancer stem-like formation in mammals. Adapted by permission from Macmillan Publishers Ltd, Nature, 2009;459:1079–84, copyright 2009.

The core NuRD complex, transcriptional factors NuRD, and stemness factors for Nanog/NuRD. Stemness factors such as Nanog, Oct4, c-myc, and sall4 are associated with the core NuRD complex in some contexts.6

The comprehensive biological and molecular view of the Mi-2/NuRD complexes and SLAC in young mammals and nematode larvae. Upper left: In mammals, the commonality, difference, and mutually induced changes among induced pluripotent stem cells, cancer stem cells, embryonic stem cells and differentiated cells (a high resolution version is presented in Supplementary Fig. 2). Adapted by permission from Macmillan Publishers Ltd: Nature Cell Biology, 2006;8:285–92, copyright 2006.53 Upper right: DAF-12/Liver X receptor and lifespan in Caenorhabditis elegans. In favorable environments, the insulin/IGF-I and transforming growth factor-beta peptide signals converge on the DAF-12/Liver X receptor for the dauer pathways. Cholesterol comes to the DAF-9/cytochrome P450 and a hormone, similar to a sterol-derived dafachronic acid product. The DAF-12/Liver X receptor directs expression of the genes involved in reproductive development, developmental advancements, fat metabolism, and accelerated aging (fast life history traits) mediated by Let-7, LIN-28, and a feedback loop that the Mi-2/NuRD complex is postulated to be involved in. In unfavorable environments, hormonal pathways are suppressed. Unliganded DAF-12 specifies programs for dauer diapause, delayed development, fat storage, and retarded aging (slow life history traits). This process is also mediated by LET-7, LIN-28, and a feedback loop that the Mi-2/NuRD complex is postulated to be involved in (see Supplementary Fig. 3). Middle: Model of the dynamic pop-up and inward gene positioning of nuclear lamina-genome interactions during self-renewal and differentiation in Caenorhabditis elegans. Two major forces drive tissue-specific subnuclear organization of the worm genome, ie, repeat-induced heterochromatin, which associates with the nuclear envelope, and tissue-specific promoters that shift inward in a dominant fashion when they are activated. Tissue-specific promoters shift in a nondominant manner to the nuclear envelope in cells in which they are inactive (Supplementary Figs. 4A and 4B). Bottom: The dynamic interchanges between euchromatin and heterochromatin in stemness and differentiation states. The putative “all-in-one Mi-2/NuRD supercomplex is highlighted” other different “isoforms” of Mi-2/NuRD complexes, include at least the activator-only Mi-2/NuRD complexes and the repressor-only Mi-2/NuRD complexes (see Supplementary Fig. 5).

The survival curve of Caenorhabditis elegans CHD-3 (eh4) after heat stress. Twenty experimental animals were used per group, ie, wild-type (N2) or CHD-3 knockout (FR355). Heat shock treatment is at 33 °C for six hours, and then incubation at 25 °C for the remainder of the experiment. If an animal could not respond to tactile stimulation, it was counted as “dead”. Experiments were repeated many times and a representative figure is shown here.

Putative antisense-silencing gene regulation (adapted from Wormbase). B0261.6, a LET-418/Mi-2β putative target gene, might encode the antisense transcripts to repress the transcription of let-363.

The model of similarity and difference between stemness pluripotency and tumorigenicity. Biological and molecular links between pluripotency and tumorigenicity are illustrated graphically. In this model, one hypothesis is that the variation/boundary of signatures could be amplified along with differentiation/tumorigenesis from those in compact stemness states.
Abbreviations: EC, embryonic carcinoma cells; hESC, human embryonic stem cells; IPSC, induced pluripotent stem cells; CSC, stem-like tumor cell/cancer stem cells.

Simplified summary of cross-talk among the Mi-2/NuRD complex, stress, and stemness, longevity/ageing, and cancer. The color green denotes promotion or activation, and the color red indicates inhibition or an abnormality.