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


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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    • "Ubiquitylation is an early and important signal in the DNA damage repair pathway. Histone 2A (H2A), and its variant H2AX, are modified by K63-linked polyubiquitin chains via multiple E3 ligases, including RING2 (also known as RNF2), RNF8 and RNF168 (Fang et al., 2004; Gatti et al., 2012; Huen et al., 2007; Mailand et al., 2007; Mattiroli et al., 2012; Oestergaard et al., 2012; Pinato et al., 2009; Plans et al., 2008), which facilitates the recruitment of DNA damage repair proteins, such as RAP80 and BRCA1. SUMO and NEDD8 are also involved in the DNA damage response (Guzzo et al., 2012; Ma et al., 2013). "
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    ABSTRACT: NEDD8 is an important regulatory factor in many biological processes. However, the substrates of neddylation and the relation between ubiquitin and NEDD8 pathways are remained largely unknown. Here, we showed that NEDD8 is covalently conjugated to H2A, and neddylation of H2A antagonizes its ubiquitination. NEDD8 suppresses H2A ubiquitination and decrease of the free NEDD8 level promotes H2A ubiquitination. We further found that E3 ligase RNF168 promotes both H2A ubiquitination and neddylation. Interestingly, RNF168 is a substrate of NEDD8 and neddylation of RNF168 is necessary for its E3 ubiquitin activity. Inhibition of RNF168 neddylation impairs the interaction between RNF168 and its E2 Ubc13. Moreover, in response to DNA damage, the level of H2A neddylation decreased with the increase of H2A ubiquitination, which facilitates DNA damage repair. And at the late stage of damage repair, H2A neddylation increased gradually while ubiquitination decreased to the basal levels. Mechanistically, NEDD8 negatively regulates DNA damage repair process by suppressing the ubiquitination of H2A and γH2AX, which further blocks the recruitment of damage-response protein BRCA1. Our findings elucidate the relation of H2A ubiquitination and neddylation, and suggest a novel modulate approach of DNA damage repair through neddylation pathway.
    Journal of Cell Science 03/2014; 127(10). DOI:10.1242/jcs.138891 · 5.43 Impact Factor
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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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