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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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KAP1 has an N-terminal tripartite motif (TRIM) containing an RBCC domain (ring finger, two B-box zinc-fingers and a coiled coil), a central HP1 (heterochromatin protein 1) domain and a C-terminal combination plant homeodomain (PHD) and bromodomain (B). These three domains have been shown to mediate nuclear localization, interaction with TFs, oligomerization and regulation of transcription.21 The RBCC domain interacts with the KRAB module present in the KRAB-C2H2 zinc-finger proteins (KZNF). In addition to the RBCC domain, every other subdomain of KAP1 contributes to the remodeling of chromatin on genomic loci targeted by the KRAB-containing TFs.9 For instance, the HP1-binding domain (PxVxL) interacts with HP1 family members, whereas the KAP1–HP1 complex has a role in silencing euchromatic and pericentric heterochromatic regions.21 The PHD and bromodomain interact with two chromatin-modifying enzymes: Mi2a and SETDB1, of which SETDB1 encodes a histone methyltransferase involved in histone methylation, gene silencing and transcriptional repression8
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fig1: KAP1 has an N-terminal tripartite motif (TRIM) containing an RBCC domain (ring finger, two B-box zinc-fingers and a coiled coil), a central HP1 (heterochromatin protein 1) domain and a C-terminal combination plant homeodomain (PHD) and bromodomain (B). These three domains have been shown to mediate nuclear localization, interaction with TFs, oligomerization and regulation of transcription.21 The RBCC domain interacts with the KRAB module present in the KRAB-C2H2 zinc-finger proteins (KZNF). In addition to the RBCC domain, every other subdomain of KAP1 contributes to the remodeling of chromatin on genomic loci targeted by the KRAB-containing TFs.9 For instance, the HP1-binding domain (PxVxL) interacts with HP1 family members, whereas the KAP1–HP1 complex has a role in silencing euchromatic and pericentric heterochromatic regions.21 The PHD and bromodomain interact with two chromatin-modifying enzymes: Mi2a and SETDB1, of which SETDB1 encodes a histone methyltransferase involved in histone methylation, gene silencing and transcriptional repression8

Mentions: Recent progress has shed light on the mechanisms by which the host evolves trans-acting repressor elements that recognize cis-acting sequences in a retrotransposon, thereby blocking its expression. The goal of this paper is to understand how the host learns to identify and repress newly invading TEs by studying the evolution of a prominent system of repressors in the human lineage. We build on recent work that has pointed to the Krueppel-Associated Protein 1 (KAP1) and its binding partners as major contributors to the formation of repressive chromatin states on ERVs.4, 5, 6, 7 Although the current understanding of the molecular mechanisms by which KAP1 and its partners repress endogenous retrotransposons has grown in recent years (see Figure 1), the evolutionary mechanisms involved in the targeting of newly inherited ERVs are still poorly understood. In this study, we propose that particular genomic locations that sit on mutational hotspots are continuously generating new zinc-finger genes with unique DNA binding affinities. A subset of these zinc-finger genes are involved in the recognition and repression of inherited ERVs by partnering with KAP1. This mechanism allows the host to generate a variety of zinc-finger motifs permitting the possible recognition of a newly inherited ERV, even before the retrovirus has colonized the host genome.


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)

KAP1 has an N-terminal tripartite motif (TRIM) containing an RBCC domain (ring finger, two B-box zinc-fingers and a coiled coil), a central HP1 (heterochromatin protein 1) domain and a C-terminal combination plant homeodomain (PHD) and bromodomain (B). These three domains have been shown to mediate nuclear localization, interaction with TFs, oligomerization and regulation of transcription.21 The RBCC domain interacts with the KRAB module present in the KRAB-C2H2 zinc-finger proteins (KZNF). In addition to the RBCC domain, every other subdomain of KAP1 contributes to the remodeling of chromatin on genomic loci targeted by the KRAB-containing TFs.9 For instance, the HP1-binding domain (PxVxL) interacts with HP1 family members, whereas the KAP1–HP1 complex has a role in silencing euchromatic and pericentric heterochromatic regions.21 The PHD and bromodomain interact with two chromatin-modifying enzymes: Mi2a and SETDB1, of which SETDB1 encodes a histone methyltransferase involved in histone methylation, gene silencing and transcriptional repression8
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: KAP1 has an N-terminal tripartite motif (TRIM) containing an RBCC domain (ring finger, two B-box zinc-fingers and a coiled coil), a central HP1 (heterochromatin protein 1) domain and a C-terminal combination plant homeodomain (PHD) and bromodomain (B). These three domains have been shown to mediate nuclear localization, interaction with TFs, oligomerization and regulation of transcription.21 The RBCC domain interacts with the KRAB module present in the KRAB-C2H2 zinc-finger proteins (KZNF). In addition to the RBCC domain, every other subdomain of KAP1 contributes to the remodeling of chromatin on genomic loci targeted by the KRAB-containing TFs.9 For instance, the HP1-binding domain (PxVxL) interacts with HP1 family members, whereas the KAP1–HP1 complex has a role in silencing euchromatic and pericentric heterochromatic regions.21 The PHD and bromodomain interact with two chromatin-modifying enzymes: Mi2a and SETDB1, of which SETDB1 encodes a histone methyltransferase involved in histone methylation, gene silencing and transcriptional repression8
Mentions: Recent progress has shed light on the mechanisms by which the host evolves trans-acting repressor elements that recognize cis-acting sequences in a retrotransposon, thereby blocking its expression. The goal of this paper is to understand how the host learns to identify and repress newly invading TEs by studying the evolution of a prominent system of repressors in the human lineage. We build on recent work that has pointed to the Krueppel-Associated Protein 1 (KAP1) and its binding partners as major contributors to the formation of repressive chromatin states on ERVs.4, 5, 6, 7 Although the current understanding of the molecular mechanisms by which KAP1 and its partners repress endogenous retrotransposons has grown in recent years (see Figure 1), the evolutionary mechanisms involved in the targeting of newly inherited ERVs are still poorly understood. In this study, we propose that particular genomic locations that sit on mutational hotspots are continuously generating new zinc-finger genes with unique DNA binding affinities. A subset of these zinc-finger genes are involved in the recognition and repression of inherited ERVs by partnering with KAP1. This mechanism allows the host to generate a variety of zinc-finger motifs permitting the possible recognition of a newly inherited ERV, even before the retrovirus has colonized the host genome.

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