There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-γ production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-γ production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-γ production induced by BCG (IFNγ-ESAT6BCG).
High-density genotyping and imputation identified ~100,000 variants within each linkage region, which we tested for association with the corresponding IFN-γ phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample.
The most convincing association observed was that between the IFNγ-ESAT6BCG phenotype and rs9828868 on chromosome 3q (p = 9.8 × 10-6 in the French sample).
This variant made a significant contribution to the linkage signal (p < 0.001), and a trend towards the same association was observed in the South African sample. This variant was reported to be an eQTL of the ZXDC gene, biologically linked to monocyte IL-12 production through CCL2/MCP1. The identification of rs9828868 as a genetic driver of IFNγ production in response to mycobacterial antigens provides new insights into human anti-tuberculosis immunity.
The zinc finger transcription factor ZXDC activates CCL2 gene expression by opposing BCL6-mediated repression.
The zinc finger X-linked duplicated (ZXD) family of transcription factors has been implicated in regulating transcription of major histocompatibility complex class II genes in antigen presenting cells; roles beyond this function are not yet known.
The expression of one gene in this family, ZXD family zinc finger C (ZXDC), is enriched in myeloid lineages and therefore we hypothesized that ZXDC may regulate myeloid-specific gene expression.
Here we demonstrate that ZXDC regulates genes involved in myeloid cell differentiation and inflammation. Overexpression of the larger isoform of ZXDC, ZXDC1, activates expression of monocyte-specific markers of differentiation and synergizes with phorbol 12-myristate 13-acetate (which causes differentiation) in the human leukemic monoblast cell line U937.
To identify additional gene targets of ZXDC1, we performed gene expression profiling which revealed multiple inflammatory gene clusters regulated by ZXDC1. Using a combination of approaches we show that ZXDC1 activates transcription of a gene within one of the regulated clusters, chemokine (C-C motif) ligand 2 (CCL2; monocyte chemoattractant protein 1; MCP1) via a previously defined distal regulatory element.
Further, ZXDC1-dependent up-regulation of the gene involves eviction of the transcriptional repressor B-cell CLL/lymphoma 6 (BCL6), a factor known to be important in resolving inflammatory responses, from this region of the promoter. Collectively, our data show that ZXDC1 is a regulator in the process of myeloid function and that ZXDC1 is responsible for Ccl2 gene de-repression by BCL6.
[Changes in genes expression caused by overexpression of the transcription factor ZXDC in embryonic kidney cell line HEK293].
The transcription factor ZXDC, a member of ZXD protein family, forms transcriptionally active complex with ZXDA and participates in the regulation of MHCII gene expression.
In this work we investigate the expression of a large group of genes in kidney embry cell of line HEK293 with overexpression of transcription factor ZXDC for identification of genes, which transcription is controlled by this transcription factor.
We have shown that overexpression of the transcription factor ZXDC in kidney embryo cell of HEK293 line significantly changes the level of expression of large group of genes, which control the behavior of different cell processes, in particular cell cycle, cell proliferation and differentiation.
The expression of most of these genes is significantly increased in the kidney cell line HEK293 with overexpression of transcription factor ZXDC, in particular EGR2, BDNF, CDKN1C and IL5Ra genes. Our results clearly demonstrated that transcription factor ZXDC plays a significant role in the regulation of expression of a large group of genes, which control important cell processes.
Sumoylation of the zinc finger protein ZXDC enhances the function of its transcriptional activation domain.
The transcription of major histocompatibility complex class II (MHC II) genes is dependent on the co-activator protein class II trans-activator (CIITA).
We have recently identified a protein known as zinc finger X-linked duplicated family member C (ZXDC) that, along with its binding partner ZXDA, forms a complex that interacts with CIITA and regulates MHC II transcription. Western blot analysis with anti-ZXDC antibodies identified two species of the ZXDC protein, one migrating near its predicted molecular mass and one with slower electrophoretic mobility. We report here that the slower migrating form is the result of sumoylation at a single lysine residue within the transcriptional activation domain of ZXDC.
Three SUMO proteins (SUMO-1, -2 and -3) can modify the ZXDC protein. Multiple SUMO E3 ligase enzymes and HDAC4 can facilitate ZXDC sumoylation, and one ligase, PIASy, interacts with a specific region of the ZXDC protein.
We found that sumoylation does not appear to disrupt or modulate the interaction of ZXDC with its binding partners. Rather, sumoylation of ZXDC is required for full activity of the transcriptional activation domain. Our findings suggest that sumoylation is an important regulator of ZXDC.
The zinc finger proteins ZXDA and ZXDC form a complex that binds CIITA and regulates MHC II gene transcription.
The transcription of major histocompatibility complex class II (MHC II) genes depends critically upon the activity of the class II trans-activator (CIITA) protein. We previously described a novel CIITA-binding protein named zinc finger X-linked duplicated family member C (ZXDC) that contributes to the activity of CIITA and the transcription of MHC II genes.
Here, we examined the contribution of a closely related family member of ZXDC, the ZXDA protein, to MHC II gene transcription. ZXDA has a domain organization similar to ZXDC, containing ten zinc fingers and a transcriptional activation domain.
Knockdown and overexpression of ZXDA demonstrated its importance in the transcriptional activation of MHC II genes. We found that ZXDA and ZXDC can self-associate, and also form a complex with each other.
The regions of the two proteins that contain zinc fingers mediate these interactions. Importantly, we found that the ZXDA-ZXDC complex interacts with CIITA, rather than either protein alone. Given our additional finding that ZXDC is present at MHC II promoters in HeLa cells, prior to and after treatment with IFN-gamma, it appears that ZXDA and ZXDC form an important regulatory complex for MHC II gene transcription.
ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription.
The class II trans-activator (CIITA) is recognized as the master regulator of major histocompatibility complex (MHC) class II gene transcription and contributes to the transcription of MHC class I genes. To better understand the function of CIITA, we performed yeast two-hybrid with the C-terminal 807 amino acids of CIITA, and cloned a novel human cDNA named zinc finger, X-linked, duplicated family member C (ZXDC).
ZXDC |
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| CSB-CL648494HU | Cusabio | 10 μg plasmid + 200μl Glycerol | Ask for price |
ZXDC siRNA |
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| 20-abx941262 | Abbexa |
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ZXDC siRNA |
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| 20-abx941263 | Abbexa |
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ZXDC Peptide |
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| MBS3234896-01mg | MyBiosource | 0.1mg | 180 EUR |
ZXDC Peptide |
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| MBS3234896-5x01mg | MyBiosource | 5x0.1mg | 730 EUR |
ZXDC Antibody |
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| E93494 | EnoGene | 100μg | 255 EUR |
ZXDC Antibody |
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| E306837 | EnoGene | 100ug/200ul | 275 EUR |
ZXDC antibody |
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| 70R-21424 | Fitzgerald | 50 ul | 289 EUR |
ZXDC antibody |
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| 70R-8902 | Fitzgerald | 50 ug | 467 EUR |
ZXDC Antibody |
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| 1-CSB-PA027161GA01HU | Cusabio |
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ZXDC Antibody |
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| 1-CSB-PA648494LA01HU | Cusabio |
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ZXDC Antibody |
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| GWB-MR909I | GenWay Biotech | 50ug | Ask for price |
ZXDC Antibody |
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| MBS7002954-005mg | MyBiosource | 0.05mg | 190 EUR |
ZXDC Antibody |
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| MBS7002954-01mg | MyBiosource | 0.1mg | 270 EUR |
ZXDC Antibody |
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| MBS7002954-5x01mg | MyBiosource | 5x0.1mg | 1205 EUR |
ZXDC Antibody |
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| MBS858904-01mg | MyBiosource | 0.1mg | 345 EUR |
ZXDC Antibody |
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| MBS858904-01mLAF405L | MyBiosource | 0.1mL(AF405L) | 565 EUR |
ZXDC Antibody |
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| MBS858904-01mLAF405S | MyBiosource | 0.1mL(AF405S) | 565 EUR |
ZXDC Antibody |
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| MBS858904-01mLAF610 | MyBiosource | 0.1mL(AF610) | 565 EUR |
ZXDC Antibody |
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| MBS858904-01mLAF635 | MyBiosource | 0.1mL(AF635) | 565 EUR |
ZXDC Antibody |
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| MBS8500388-01mg | MyBiosource | 0.1mg | 325 EUR |
The 858 amino acid ZXDC protein contains 10 zinc fingers and a transcriptional activation domain, and was found to interact with the region of CIITA containing leucine-rich repeats. Over-expression of ZXDC in human cell lines resulted in super-activation of MHC class I and class II promoters by CIITA.
Conversely, silencing of ZXDC expression reduced the ability of CIITA to activate transcription of MHC class II genes. Given the specific interaction between the ZXDC and CIITA proteins, as well as the effect of ZXDC on MHC gene transcription, it appears that ZXDC is an important regulator of both MHC class I and class II transcription.