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Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2.

ABSTRACT: Nested genes are fairly common within the mammalian nervous system, yet few studies have examined whether the guest and host genes might be coordinately regulated. Tissue inhibitors of metalloproteinase (TIMPs) inhibit extracellular matrix proteolysis mediated by metzincin proteases. TIMP-2 is the only TIMP not nested within a synapsin gene. It does, however, serve as a host for differential display clone 8 (DDC8), a testis-specific gene whose expression is upregulated during spermatogenesis. Here, we demonstrate that DDC8 is not testis specific. Furthermore, DDC8 expression in nonneural and neural tissues mimics that of TIMP-2, including its upregulation in response to traumatic brain injury, suggesting a potential regulatory relationship. The most striking observation is that the TIMP-2 knockout mouse brain contains TIMP-2 mRNA encoding exons 2-5, which are downstream of DDC8, but not exon 1, which contains the signal sequence and cysteine residue required for MMP inhibition, indicating a functional knockout. That TIMP-2 transcripts in wild-type brain contain DDC8 sequence suggests alternative splicing between the two genes.

SUBMITTER: Jaworski DM

PROVIDER: S-EPMC3880020 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2.

Jaworski Diane M DM Beem-Miller Micah M Lluri Gentian G Barrantes-Reynolds Ramiro R

Physiological genomics 20060919 2

Nested genes are fairly common within the mammalian nervous system, yet few studies have examined whether the guest and host genes might be coordinately regulated. Tissue inhibitors of metalloproteinase (TIMPs) inhibit extracellular matrix proteolysis mediated by metzincin proteases. TIMP-2 is the only TIMP not nested within a synapsin gene. It does, however, serve as a host for differential display clone 8 (DDC8), a testis-specific gene whose expression is upregulated during spermatogenesis. He ...[more]

PMID: 16985004

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Project description:During HIV-1 infection, there is a massive perturbation of host gene expression, but as yet, genome-wide studies have not identified host genes affecting HIV-1 replication in lymphatic tissue, the primary site of virus-host interactions. In this study, we isolated RNA from the inguinal lymph nodes of 22 HIV-1-infected individuals and utilized a microarray approach to identify host genes critically important for viral replication in lymphatic tissue by examining gene expression associated with viral load. Strikingly, ~95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset (1) inhibit cellular activation/proliferation (ex.: TCFL5, SOCS5 and SCOS7, KLF10), (2) promote heterochromatin formation (ex.: HIC2, CREBZF, ZNF148/ZBP-89), (3) increase collagen synthesis (ex.: PLOD2, POSTN, CRTAP), and (4) reduce cellular transcription and translation. Potential anti-HIV-1 restriction factors were also identified (ex.: NR3C1, HNRNPU, PACT). Only ~5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all these genes function in innate and adaptive immunity, particularly highlighting a heightened interferon system. The predominance of negative correlations as well as the disconnect between host defenses and viral load point to the importance of genes that regulate target cell activation and genes that code for potentially new restriction factors as determinants of viral load rather than conventional host defenses. Total RNA was isolated from the inguinal lymph nodes of 22 HIV-1-infected subjects at different clinical stages (and varying viral loads) and prepared for RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 microarrays. Replicate arrays were performed for lymph node samples to minimize assay noise and host genes critically important for viral replication in lymphatic tissue were identified by examining gene expression and its association with viral load. Replicates were not performed for samples WB91 and TS35 due to limited amounts of biomaterial.

Dataset Information

Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2.

Publications

Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2.

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