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The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses.

Lukic S, Nicolas JC, Levine AJ - Cell Death Differ. (2013)

Bottom Line: Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes.Many of these zinc-finger genes exist in clusters associated with human chromosome 19.In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.

ABSTRACT
Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

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Abundance of binding DNA associated with mutant KAP1 (red) and wild-type KAP1 (blue) in different families of repetitive elements. Only ∼1% of DNA on binding sites annotated as TEs (LTR elements, LINE, SINE and DNA transposons) that was present in the ChIP-seq peaks associated with wt KAP1 was also present in the peaks associated with mt KAP1. The abundance of DNA-binding sequence was measured in units of millions of base pairs (Mbp)
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fig2: Abundance of binding DNA associated with mutant KAP1 (red) and wild-type KAP1 (blue) in different families of repetitive elements. Only ∼1% of DNA on binding sites annotated as TEs (LTR elements, LINE, SINE and DNA transposons) that was present in the ChIP-seq peaks associated with wt KAP1 was also present in the peaks associated with mt KAP1. The abundance of DNA-binding sequence was measured in units of millions of base pairs (Mbp)

Mentions: The next question we explored was what factors that interact with KAP1 recognize this parasitic DNA? The available evidence demonstrates that the recruitment of KAP1 to endogenous retroviral DNA is mediated by the interaction of its RBCC domain with the Krueppel-Associated Box (KRAB) domain present in many TFs.9 To test this hypothesis, we compared the binding sites of a mutant KAP1 with no RBCC domain (mt KAP1) versus the binding sites of wild-type KAP1 (wt KAP1) on HEK293 cells8 (see Materials and Methods section). We inferred the binding peaks using the MACS algorithm.10 We applied a P-value cutoff of 10−10 and identified a total of 20 139 autosomal peaks for wt KAP1 and 732 autosomal peaks for mt KAP1. To reduce the fraction of misidentified peaks, we considered only the subset of peaks that had also been inferred previously. We observed a very large depletion of binding sites for the mutant KAP1-ΔRBCC (mt KAP1). In particular, mt KAP1 was found in only ∼4% of the binding sites on TE-coding DNA compared with experiments where wild-type KAP1 was used (wt KAP1) (see Figure 2). In the case of LTRs and LINEs, only ∼3.5% of the wt binding sites on LTR elements were present in the experiment with mt KAP1. Hence, this supports the hypothesis that KAP1 is recruited to endogenous retroviral DNA by KRAB-containing TFs. This observation is consistent with experiments on mouse cells, in which the knockout of KAP1 gave rise to the transcriptional derepression of LINEs and ERVs.4


The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses.

Lukic S, Nicolas JC, Levine AJ - Cell Death Differ. (2013)

Abundance of binding DNA associated with mutant KAP1 (red) and wild-type KAP1 (blue) in different families of repetitive elements. Only ∼1% of DNA on binding sites annotated as TEs (LTR elements, LINE, SINE and DNA transposons) that was present in the ChIP-seq peaks associated with wt KAP1 was also present in the peaks associated with mt KAP1. The abundance of DNA-binding sequence was measured in units of millions of base pairs (Mbp)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921586&req=5

fig2: Abundance of binding DNA associated with mutant KAP1 (red) and wild-type KAP1 (blue) in different families of repetitive elements. Only ∼1% of DNA on binding sites annotated as TEs (LTR elements, LINE, SINE and DNA transposons) that was present in the ChIP-seq peaks associated with wt KAP1 was also present in the peaks associated with mt KAP1. The abundance of DNA-binding sequence was measured in units of millions of base pairs (Mbp)
Mentions: The next question we explored was what factors that interact with KAP1 recognize this parasitic DNA? The available evidence demonstrates that the recruitment of KAP1 to endogenous retroviral DNA is mediated by the interaction of its RBCC domain with the Krueppel-Associated Box (KRAB) domain present in many TFs.9 To test this hypothesis, we compared the binding sites of a mutant KAP1 with no RBCC domain (mt KAP1) versus the binding sites of wild-type KAP1 (wt KAP1) on HEK293 cells8 (see Materials and Methods section). We inferred the binding peaks using the MACS algorithm.10 We applied a P-value cutoff of 10−10 and identified a total of 20 139 autosomal peaks for wt KAP1 and 732 autosomal peaks for mt KAP1. To reduce the fraction of misidentified peaks, we considered only the subset of peaks that had also been inferred previously. We observed a very large depletion of binding sites for the mutant KAP1-ΔRBCC (mt KAP1). In particular, mt KAP1 was found in only ∼4% of the binding sites on TE-coding DNA compared with experiments where wild-type KAP1 was used (wt KAP1) (see Figure 2). In the case of LTRs and LINEs, only ∼3.5% of the wt binding sites on LTR elements were present in the experiment with mt KAP1. Hence, this supports the hypothesis that KAP1 is recruited to endogenous retroviral DNA by KRAB-containing TFs. This observation is consistent with experiments on mouse cells, in which the knockout of KAP1 gave rise to the transcriptional derepression of LINEs and ERVs.4

Bottom Line: Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes.Many of these zinc-finger genes exist in clusters associated with human chromosome 19.In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.

ABSTRACT
Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

Show MeSH
Related in: MedlinePlus