Confining euchromatin/heterochromatin territory: jumonji crosses the line - PubMed (original) (raw)

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Confining euchromatin/heterochromatin territory: jumonji crosses the line

Hisashi Tamaru. Genes Dev. 2010.

Abstract

Heterochromatin is typically highly condensed, gene-poor, and transcriptionally silent, whereas euchromatin is less condensed, gene-rich, and more accessible to transcription. Besides acting as a graveyard for selfish mobile DNA repeats, heterochromatin contributes to important biological functions, such as chromosome segregation during cell division. Multiple features of heterochromatin-including the presence or absence of specific histone modifications, DNA methylation, and small RNAs-have been implicated in distinguishing heterochromatin from euchromatin in various organisms. Cells malfunction if the genome fails to restrict repressive chromatin marks within heterochromatin domains. How euchromatin and heterochromatin territories are confined remains poorly understood. Recent studies from the fission yeast Schizosaccharomyces pombe, the flowering plant Arabidopsis thaliana, and the filamentous fungus Neurospora crassa have revealed a new role for Jumonji C (JmjC) domain-containing proteins in protecting euchromatin from heterochromatin marks.

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Figures

Figure 1.

Figure 1.

Model for the involvement of DMM-1 in preventing spreading of heterochromatin into euchromatin. In N. crassa, chromatin regions containing A:T-rich DNA sequences (pink fiber) that have been subjected to RIP constitute heterochromatin (nucleosomes in blue). RNAi components are dispensable for heterochromatin targeting. It is thought that an unidentified protein (X) that recognizes TpA/ApT base pairs recruits DIM-5 HMT to establish H3K9me. HP1 forms a complex with the DMT DIM-2 and binds to H3K9me via its chromodomain, allowing DIM-2 to methylate nucleosomal DNA (5mC) in all sequence contexts. HP1 also recruits DMM-1 and its associated protein, DMM-2, to RIP'd heterochromatic regions. The HP1/DMM-1/DMM-2 complex is preferentially localized to edges of heterochromatin to block HP1/DIM-2 and/or DIM-5 activity. DMM-1/DMM-2 may bind to both RIP'd and non-RIP'd sites of heterochromatin/euchromatin boundaries through the DMM-1 cysteine-rich domains that are implicated in binding to an unidentified histone mark (question mark) and the DMM-2 Zn(II)2Cys6 DNA-binding motif, respectively. A dmm-1 mutation allows HP1/DIM-2 to spread across non-RIP'd euchromatic regions (nucleosomes in yellow) and methylate non-RIP'd DNA (black fiber). In this situation, 5mC attracts DIM-5 to methylate H3K9, presumably via an unidentified DNA methyl-binding protein (Y). Heterochromatin spreading can silence nearby genes. Although the JmjC domain of DMM-1 is required for its function, histone lysine demethylase (KDM) activity has not been detected for DMM-1 (Honda et al. 2010).

Figure 2.

Figure 2.

Model for the involvement of Epe1 in preventing spreading of heterochromatin into euchromatin. In S. pombe, the IRC elements (pink fiber) located at the boundaries of heterochromatin are transcribed by Pol II within the context of heterochromatin, are processed into siRNAs by the RITS complex, and serve as heterochromatin barrier elements. A DNA-binding factor or the RNAi pathway targets Clr4 HMT to heterochromatic regions (nucleosomes in blue) for H3K9me, which provides a binding site for the chromodomain of Swi6 (homolog of HP1). Swi6 recruits the JmjC domain protein Epe1. The histone deacetylase Clr3 is recruited by Swi6 and another chromodomain protein, Chp2. Clr3 limits Pol II accessibility to heterochromatic repeats and the IRC barrier elements, whereas Epe1 promotes its transcription. There is evidence for an unidentified protein (questionmark) that specifically targets Epe1 to heterochromatin/euchromatin boundaries. High concentrations of Epe1 and the resulting high levels of transcription at _IRC_s presumably provide an “open” chromatin environment that counteracts the repressive effects of heterochromatin. The balance between the opposing activities of Clr3 and Epe1 is critical for confining heterochromatin and its associated factors within a defined territory (Zofall and Grewal 2006). An epe1 mutation leads predominantly to spreading of heterochromatin across euchromatic regions (nucleosomes in yellow) through self-reinforcing reactions between H3K9me and Swi6. Binding of the Clr4 chromodomain to H3K9me facilitates methylation of adjacent nucleosomes. Heterochromatin spreading can cause silencing of neighboring genes. It may be envisioned that, in a small population of cells, loss of Epe1 completely shuts off transcription of heterochromatic repeats and subsequent processing into siRNAs, which are essential for the stable maintenance of heterochromatin, thereby resulting in heterochromatin contraction. Histone lysine demethylase (KDM) activity has not been detected with Epe1 (Zofall and Grewal 2006).

Figure 3.

Figure 3.

Model for the involvement of IBM1 in protecting transcribed genes from CHG methylation. In A. thaliana, DNA 5mC of genes is limited to CG sites. IBM1 prevents KYP HMT from inappropriate deposition of H3K9me on the bodies of active genes by either suppressing KYP activity or demethylating H3K9me in a transcription-coupled manner. It is not known whether IBM and KYP interact with Pol II. An ibm1 mutation allows KYP to methylate H3K9 within transcribed regions. The chromodomain of the DMT CMT3 recognizes dual methylation marks at H3K9 and H3K27, and methylates DNA preferentially in the CHG context. The SRA domain of KYP binds to 5mC to facilitate methylation of adjacent nucleosomes. The ectopic CHG methylation of the gene body is not invariably associated with transcriptional repression. The central portions of long transcribed genes are most frequently subjected to _ibm1_-induced de novo methylation by unknown mechanisms. RdDM components do not seem to be involved in the process. The JmjC domain of IBM1 has all of the key amino acid residues critical for lysine demethylase (KDM) activity, but the activity has not been detected with IBM1 (Saze et al. 2008; Miura et al. 2009). (P) Promoter; (T) terminator.

Figure 4.

Figure 4.

Abnormal groove formation on the neural plate of jumonji homozygous mutant mouse embryos. Scanning electron micrographs of dorsal views of wild-type (A) and jumonji mutant (B) mouse embryos at embryonic day 8.5 (nine-somite stage). Bar, 100 μm. Photographs courtesy of Takashi Takeuchi.

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