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Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome.

Brideau NJ, Coker H, Gendrel AV, Siebert CA, Bezstarosti K, Demmers J, Poot RA, Nesterova TB, Brockdorff N - Mol. Cell. Biol. (2015)

Bottom Line: We further show that the principal mechanism for chromatin loading of SMCHD1 involves an LRIF1-mediated interaction with HP1γ at trimethylated histone H3 lysine 9 (H3K9me3)-modified chromatin sites on the chromosome arms.A parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome.Together, our results provide key insights into SMCHD1 function and target site selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

No MeSH data available.


Related in: MedlinePlus

Model for SMCHD1 recruitment to chromatin. (A) Constitutive heterochromatin such as that found at pericentromeric regions is marked by H3K9me3 and all three HP1 paralogs. Recruitment of SMCHD1 (blue) to these sites by LRIF1 may be blocked by the compact and inaccessible organization of HP1 protein oligomers. (B) Other heterochromatic sites, such as telomeres and subtelomeric D4Z4 repeats, are marked by H3K9me2 and H3K9me3 and HP1γ. SMCHD1 recruitment to these sites is mediated by LRIF1 and is independent of the ATPase and BAH domains. (C) SMCHD1 recruitment to Xi in mouse, which is marked with H3K27me3 and H3K9me2, is independent of LRIF1 but requires ATPase activity and the BAH domain. The molecular mechanism behind SMCHD1 loading onto Xi is unknown but may be an active process similar to the loading of conventional SMC proteins via hinge opening.
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Figure 9: Model for SMCHD1 recruitment to chromatin. (A) Constitutive heterochromatin such as that found at pericentromeric regions is marked by H3K9me3 and all three HP1 paralogs. Recruitment of SMCHD1 (blue) to these sites by LRIF1 may be blocked by the compact and inaccessible organization of HP1 protein oligomers. (B) Other heterochromatic sites, such as telomeres and subtelomeric D4Z4 repeats, are marked by H3K9me2 and H3K9me3 and HP1γ. SMCHD1 recruitment to these sites is mediated by LRIF1 and is independent of the ATPase and BAH domains. (C) SMCHD1 recruitment to Xi in mouse, which is marked with H3K27me3 and H3K9me2, is independent of LRIF1 but requires ATPase activity and the BAH domain. The molecular mechanism behind SMCHD1 loading onto Xi is unknown but may be an active process similar to the loading of conventional SMC proteins via hinge opening.

Mentions: Nuclear fractionation analysis demonstrates that a major pool of SMCHD1 protein is stably bound to chromatin. Neither GHKL ATPase activity nor the BAH domain is required for this association. However, deletion of LRIF1 or of the SMCHD1 hinge domain region that is required for LRIF1 interactions results in a redistribution of the bulk of SMCHD1 to the soluble nucleoplasm. These findings suggest that LRIF1, in conjunction with HP1γ located principally on chromosome arms, functions as an SMCHD1 loading complex (Fig. 9B). This may be analogous to the role of Scc2/4 in loading the cohesin complex (50). We suggest that LRIF1-dependent loading establishes an initial association of SMCHD1 with chromatin that is subsequently maintained independently of LRIF1. One possibility is that loading results in a topological trapping of the chromatin fiber by the SMCHD1 dimer, similar to cohesin and possibly other canonical SMC complexes (Fig. 9B). We further suggest that the GHKL ATPase and/or the BAH domain plays a role in SMCHD1 dynamics/unloading, as neither is required for the stable association of SMCHD1 with chromatin.


Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome.

Brideau NJ, Coker H, Gendrel AV, Siebert CA, Bezstarosti K, Demmers J, Poot RA, Nesterova TB, Brockdorff N - Mol. Cell. Biol. (2015)

Model for SMCHD1 recruitment to chromatin. (A) Constitutive heterochromatin such as that found at pericentromeric regions is marked by H3K9me3 and all three HP1 paralogs. Recruitment of SMCHD1 (blue) to these sites by LRIF1 may be blocked by the compact and inaccessible organization of HP1 protein oligomers. (B) Other heterochromatic sites, such as telomeres and subtelomeric D4Z4 repeats, are marked by H3K9me2 and H3K9me3 and HP1γ. SMCHD1 recruitment to these sites is mediated by LRIF1 and is independent of the ATPase and BAH domains. (C) SMCHD1 recruitment to Xi in mouse, which is marked with H3K27me3 and H3K9me2, is independent of LRIF1 but requires ATPase activity and the BAH domain. The molecular mechanism behind SMCHD1 loading onto Xi is unknown but may be an active process similar to the loading of conventional SMC proteins via hinge opening.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4628070&req=5

Figure 9: Model for SMCHD1 recruitment to chromatin. (A) Constitutive heterochromatin such as that found at pericentromeric regions is marked by H3K9me3 and all three HP1 paralogs. Recruitment of SMCHD1 (blue) to these sites by LRIF1 may be blocked by the compact and inaccessible organization of HP1 protein oligomers. (B) Other heterochromatic sites, such as telomeres and subtelomeric D4Z4 repeats, are marked by H3K9me2 and H3K9me3 and HP1γ. SMCHD1 recruitment to these sites is mediated by LRIF1 and is independent of the ATPase and BAH domains. (C) SMCHD1 recruitment to Xi in mouse, which is marked with H3K27me3 and H3K9me2, is independent of LRIF1 but requires ATPase activity and the BAH domain. The molecular mechanism behind SMCHD1 loading onto Xi is unknown but may be an active process similar to the loading of conventional SMC proteins via hinge opening.
Mentions: Nuclear fractionation analysis demonstrates that a major pool of SMCHD1 protein is stably bound to chromatin. Neither GHKL ATPase activity nor the BAH domain is required for this association. However, deletion of LRIF1 or of the SMCHD1 hinge domain region that is required for LRIF1 interactions results in a redistribution of the bulk of SMCHD1 to the soluble nucleoplasm. These findings suggest that LRIF1, in conjunction with HP1γ located principally on chromosome arms, functions as an SMCHD1 loading complex (Fig. 9B). This may be analogous to the role of Scc2/4 in loading the cohesin complex (50). We suggest that LRIF1-dependent loading establishes an initial association of SMCHD1 with chromatin that is subsequently maintained independently of LRIF1. One possibility is that loading results in a topological trapping of the chromatin fiber by the SMCHD1 dimer, similar to cohesin and possibly other canonical SMC complexes (Fig. 9B). We further suggest that the GHKL ATPase and/or the BAH domain plays a role in SMCHD1 dynamics/unloading, as neither is required for the stable association of SMCHD1 with chromatin.

Bottom Line: We further show that the principal mechanism for chromatin loading of SMCHD1 involves an LRIF1-mediated interaction with HP1γ at trimethylated histone H3 lysine 9 (H3K9me3)-modified chromatin sites on the chromosome arms.A parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome.Together, our results provide key insights into SMCHD1 function and target site selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

No MeSH data available.


Related in: MedlinePlus