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?-Globin cis-elements determine differential nuclear targeting through epigenetic modifications.

ABSTRACT: Increasing evidence points to nuclear compartmentalization as a contributing mechanism for gene regulation, yet mechanisms for compartmentalization remain unclear. In this paper, we use autonomous targeting of bacterial artificial chromosome (BAC) transgenes to reveal cis requirements for peripheral targeting. Three peripheral targeting regions (PTRs) within an HBB BAC bias a competition between pericentric versus peripheral heterochromatin targeting toward the nuclear periphery, which correlates with increased H3K9me3 across the ?-globin gene cluster and locus control region. Targeting to both heterochromatin compartments is dependent on Suv39H-mediated H3K9me3 methylation. In different chromosomal contexts, PTRs confer no targeting, targeting to pericentric heterochromatin, or targeting to the periphery. A combination of fluorescent in situ hybridization, BAC transgenesis, and knockdown experiments reveals that peripheral tethering of the endogenous HBB locus depends both on Suv39H-mediated H3K9me3 methylation over hundreds of kilobases surrounding HBB and on G9a-mediated H3K9me2 methylation over flanking sequences in an adjacent lamin-associated domain. Our results demonstrate that multiple cis-elements regulate the overall balance of specific epigenetic marks and peripheral gene targeting.

SUBMITTER: Bian Q

PROVIDER: S-EPMC3857487 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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β-Globin cis-elements determine differential nuclear targeting through epigenetic modifications.

Bian Qian Q Khanna Nimish N Alvikas Jurgis J Belmont Andrew S AS

The Journal of cell biology 20131202 5

Increasing evidence points to nuclear compartmentalization as a contributing mechanism for gene regulation, yet mechanisms for compartmentalization remain unclear. In this paper, we use autonomous targeting of bacterial artificial chromosome (BAC) transgenes to reveal cis requirements for peripheral targeting. Three peripheral targeting regions (PTRs) within an HBB BAC bias a competition between pericentric versus peripheral heterochromatin targeting toward the nuclear periphery, which correlate ...[more]

PMID: 24297746

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Project description:BACKGROUND:Transposition is disruptive in nature and, thus, it is imperative for host genomes to evolve mechanisms that suppress the activity of transposable elements (TEs). At the same time, transposition also provides diverse sequences that can be exapted by host genomes as functional elements. These notions form the basis of two competing hypotheses pertaining to the role of epigenetic modifications of TEs in eukaryotic genomes: the genome defense hypothesis and the exaptation hypothesis. To date, all available evidence points to the genome defense hypothesis as the best explanation for the biological role of TE epigenetic modifications. RESULTS:We evaluated several predictions generated by the genome defense hypothesis versus the exaptation hypothesis using recently characterized epigenetic histone modification data for the human genome. To this end, we mapped chromatin immunoprecipitation sequence tags from 38 histone modifications, characterized in CD4+ T cells, to the human genome and calculated their enrichment and depletion in all families of human TEs. We found that several of these families are significantly enriched or depleted for various histone modifications, both active and repressive. The enrichment of human TE families with active histone modifications is consistent with the exaptation hypothesis and stands in contrast to previous analyses that have found mammalian TEs to be exclusively repressively modified. Comparisons between TE families revealed that older families carry more histone modifications than younger ones, another observation consistent with the exaptation hypothesis. However, data from within family analyses on the relative ages of epigenetically modified elements are consistent with both the genome defense and exaptation hypotheses. Finally, TEs located proximal to genes carry more histone modifications than the ones that are distal to genes, as may be expected if epigenetically modified TEs help to regulate the expression of nearby host genes. CONCLUSIONS:With a few exceptions, most of our findings support the exaptation hypothesis for the role of TE epigenetic modifications when vetted against the genome defense hypothesis. The recruitment of epigenetic modifications may represent an additional mechanism by which TEs can contribute to the regulatory functions of their host genomes.

Dataset Information

?-Globin cis-elements determine differential nuclear targeting through epigenetic modifications.

Publications

β-Globin cis-elements determine differential nuclear targeting through epigenetic modifications.

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