Fang, J., Chen, T., Chadwick, B., Li, E. & Zhang, Y. Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J. Biol. Chem. 279, 52812-52815

Duke University, Durham, North Carolina, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2005; 279(51):52812-5. DOI: 10.1074/jbc.C400493200
Source: PubMed

ABSTRACT Histone modifications are thought to serve as epigenetic markers that mediate dynamic changes in chromatin structure and regulation
of gene expression. As a model system for understanding epigenetic silencing, X chromosome inactivation has been previously
linked to a number of histone modifications including methylation and hypoacetylation. In this study, we provide evidence
that supports H2A ubiquitination as a novel epigenetic marker for the inactive X chromosome (Xi) and links H2A ubiquitination
to initiation of X inactivation. We found that the H2A-K119 ubiquitin E3 ligase Ring1b, a Polycomb group protein, is enriched
on Xi in female trophoblast stem (TS) cells as well as differentiating embryonic stem (ES) cells. Consistent with Ring1b mediating
H2A ubiquitination, ubiquitinated H2A (ubH2A) is also enriched on the Xi of both TS and ES cells. We demonstrate that the
enrichment of Ring1b and ubH2A on Xi is transient during TS and ES cell differentiation, suggesting that the Ring1b and ubH2A
are involved in the initiation of both imprinted and random X inactivation. Furthermore, we showed that the association of
Ring1b and ubH2A with Xi is mitotically stable in non-differentiated TS cells.

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    • "The H3K27me2/3 mark is specifically recognized by the chromodomain of Polycomb (Pc), a subunit of PRC1 complexes, providing a platform for recruitment of the PRC1 complex (Wang et al., 2004). The PRC1 complex then ubiquitylates histone H2A on Lys119 (de Napoles et al., 2004; Fang et al., 2004) leading to Polycomb-mediated transcriptional repression. PRC1, however, can also be recruited in the absence of PRC2 and H3K27me3-enriched chromatin regions (Schoeftner et al., 2006). "
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    ABSTRACT: During embryonic development a large number of widely differing and specialized cell types with identical genomes are generated from a single totipotent zygote. Tissue specific transcription factors cooperate with epigenetic modifiers to establish cellular identity in differentiated cells and epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns, a phenomenon referred to as epigenetic memory. This is accomplished via the stable maintenance of various epigenetic marks through successive rounds of cell division. Preservation of DNA methylation patterns is a well-established mechanism of epigenetic memory, but more recently it has become clear that many other epigenetic modifications can also be maintained following DNA replication and cell division. In this review, we present an overview of the current knowledge regarding the role of histone lysine methylation in the establishment and maintenance of stable epigenetic states.
    Frontiers in Genetics 02/2014; 5:19. DOI:10.3389/fgene.2014.00019
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    • "The inactive X-chromosome (Xi) in somatic cells and extraembryonic endoderm (XEN) cells which represent random and imprinted XCI, respectively, is depleted in the modifications characteristic of active chromatin. The modifications associated with the inactive chromatin are distributed along Xi as discrete bands and form two types of facultative heterochromatin [11], [12], [13], [14], [15], [16], [17], [18]. The first type corresponds to gene-rich G-light bands. "
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    ABSTRACT: In rodent female mammals, there are two forms of X-inactivation - imprinted and random which take place in extraembryonic and embryonic tissues, respectively. The inactive X-chromosome during random X-inactivation was shown to contain two types of facultative heterochromatin that alternate and do not overlap. However, chromatin structure of the inactive X-chromosome during imprinted X-inactivation, especially at early stages, is still not well understood. In this work, we studied chromatin modifications associated with the inactive X-chromosome at different stages of imprinted X-inactivation in a rodent, Microtus levis. It has been found that imprinted X-inactivation in vole occurs in a species-specific manner in two steps. The inactive X-chromosome at early stages of imprinted X-inactivation is characterized by accumulation of H3K9me3, HP1, H4K20me3, and uH2A, resembling to some extent the pattern of repressive chromatin modifications of meiotic sex chromatin. Later, the inactive X-chromosome recruits trimethylated H3K27 and acquires the two types of heterochromatin associated with random X-inactivation.
    PLoS ONE 02/2014; 9(2):e88256. DOI:10.1371/journal.pone.0088256 · 3.23 Impact Factor
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    • "The Cdx2-based TRM for TSCs included some proteins essential for the determination and function of trophoblast cells. For instance, Runx1 is known to regulate the expression of Ada, a gene expressed in placental trophoblast cells that plays a fundamental role in the developing embryo (55), Smarca4 is important for TSC maintenance (56) and Rnf2 (also known as Ring1b, a polycomb protein) inactivates the X chromosome in developing female embryos (57). The Sox2-based TRM for NPCs is remarkably different from the Sox2 TRM from ESCs: whereas nuclear receptors with C4 zinc fingers were predicted in ESCs (including Esrra and Esrrb), other TF families seem to be specific to the Sox2 TRM of NPCs, including bHLH (Tcf3, Tcf4), Fork head (Hoxa1, Hoxa5), Paired box (Pax6), SAND (Gmeb2), Tryptophan cluster (Etv6) and STAT (Stat3). "
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    ABSTRACT: Transcription factors (TFs) combine with co-factors to form transcriptional regulatory modules (TRMs) that regulate gene expression programs with spatiotemporal specificity. Here we present a novel and generic method (rTRM) for the reconstruction of TRMs that integrates genomic information from TF binding, cell type-specific gene expression and protein-protein interactions. rTRM was applied to reconstruct the TRMs specific for embryonic stem cells (ESC) and hematopoietic stem cells (HSC), neural progenitor cells, trophoblast stem cells and distinct types of terminally differentiated CD4(+) T cells. The ESC and HSC TRM predictions were highly precise, yielding 77 and 96 proteins, of which ∼75% have been independently shown to be involved in the regulation of these cell types. Furthermore, rTRM successfully identified a large number of bridging proteins with known roles in ESCs and HSCs, which could not have been identified using genomic approaches alone, as they lack the ability to bind specific DNA sequences. This highlights the advantage of rTRM over other methods that ignore PPI information, as proteins need to interact with other proteins to form complexes and perform specific functions. The prediction and experimental validation of the co-factors that endow master regulatory TFs with the capacity to select specific genomic sites, modulate the local epigenetic profile and integrate multiple signals will provide important mechanistic insights not only into how such TFs operate, but also into abnormal transcriptional states leading to disease.
    Nucleic Acids Research 10/2013; 42(1). DOI:10.1093/nar/gkt913 · 9.11 Impact Factor
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