DNAJC27 Human

What is DNAJC27 and what is its molecular classification?

DNAJC27, also known as DnaJ (Hsp40) homolog subfamily C member 27, is a protein-coding gene located on chromosome 17 in humans. It belongs to the heat shock protein 40 (HSP40) family, which plays an essential role in the heat shock response pathway. The protein is predicted to enable GTPase activity and contains several important domains, including a DnaJ domain, a small GTP-binding domain, and a P-loop containing nucleoside triphosphate hydrolase . DNAJC27 is also known as RBJ (Ras-associated (RalGDS/AF-6) domain and Pleckstrin homology domain containing protein J) in some literature, highlighting its structural features.

What are the predicted cellular functions of DNAJC27?

Based on current research, DNAJC27 is predicted to be involved in multiple cellular processes including Rab protein signal transduction and intracellular protein transport. It is predicted to localize primarily to the nucleus . Recent investigations have expanded our understanding of DNAJC27's function, revealing its potential role in metabolic regulation and inflammatory processes. Unlike some other members of the HSP40 family that exhibit anti-inflammatory properties, DNAJC27 appears to have pro-inflammatory roles in conditions like obesity and Type 2 Diabetes (T2D) .

How is DNAJC27 structurally different from other DnaJ family proteins?

DNAJC27 contains several distinctive domains that differentiate it from other members of the HSP40 family. Domain analysis reveals the presence of a Chaperone J-domain superfamily domain, a DnaJ domain, a P-loop containing nucleoside triphosphate hydrolase, a Small GTPase domain, and a Small GTP-binding domain . This combination of domains is relatively unique within the HSP40 family, particularly the presence of GTPase-related domains, suggesting specialized functions beyond the typical chaperone activities associated with HSP proteins.

What methodologies are recommended for measuring DNAJC27 expression in human tissues?

For researchers examining DNAJC27 expression, multiple complementary techniques have proven effective:

Protein Level Measurement:

• ELISA: For quantitative measurement of circulating DNAJC27 in plasma, specialized ELISA kits can be employed. Research protocols typically involve diluting plasma samples by a factor of four with appropriate diluent before proceeding with standard ELISA procedures .

• Western Blot: This technique is effective for analyzing DNAJC27 protein expression in peripheral blood mononuclear cells (PBMCs) and tissue samples, with GAPDH commonly used as a normalization control .

Gene Expression Analysis:

• qRT-PCR: For measuring DNAJC27 mRNA expression in PBMCs and adipose tissue, researchers typically express results as ΔΔCT values or fold changes relative to control groups .

To ensure meaningful results, it's recommended to analyze DNAJC27 expression across multiple sample types when possible, as studies have shown correlation between circulating levels and tissue expression.

In which human tissues is DNAJC27 predominantly expressed?

DNAJC27 expression has been documented in multiple human tissues, with significant expression noted in:

• Peripheral Blood Mononuclear Cells (PBMCs): Research has shown detectable expression of DNAJC27 in PBMCs, with differential expression observed between obese and non-obese individuals .

• Adipose Tissue: Studies have confirmed DNAJC27 expression in adipose tissue, with upregulation noted in the context of obesity .

• Circulation: DNAJC27 protein is detectable in plasma, with levels correlating with its expression in both PBMCs and adipose tissue .

The expression pattern suggests DNAJC27 may have systemic effects, with both PBMCs and adipose tissue potentially serving as sources of circulating DNAJC27 protein. Research has demonstrated a positive correlation between DNAJC27 expression in PBMCs and adipose tissue (r = 0.777; P < 0.001), indicating coordinated regulation across these tissues .

What evidence links DNAJC27 to obesity and metabolic syndrome?

Multiple lines of evidence establish DNAJC27's relationship with obesity and metabolic disorders:

Genetic Associations:

• Genome-Wide Association Studies (GWAS) have identified DNAJC27 to be associated with BMI in East Asian populations .

• The gene is located near adenylyl cyclase 3 (ADCY3), which interacts with MC4R, a key regulator of appetite and energy homeostasis .

Expression Studies:

• DNAJC27 plasma levels are significantly elevated in obese individuals (6.90 ± 1.3 ng/mL) compared to non-obese subjects (3.81 ± 0.43 ng/mL) in non-diabetic populations (P = 0.033) .

• Protein expression in PBMCs shows significant upregulation in obese subjects .

• Gene expression analysis reveals approximately 2-fold higher expression in obese individuals compared to non-obese controls in both PBMCs (P = 0.006) and adipose tissue (1.7-fold, P = 0.04) .

Clinical Correlations:

• DNAJC27 levels positively correlate with fasting blood glucose (r = 0.316, P = 0.009), HOMA-IR (r = 0.316, P = 0.01), and triglyceride levels (r = 0.215, P = 0.05) .

• Strong positive associations exist between DNAJC27 and obesity biomarkers including leptin (r = 0.600, P < 0.0001) and resistin (r = 0.466, P = 0.002) .

These findings collectively suggest DNAJC27 plays a role in the pathophysiology of obesity and related metabolic disorders.

How does DNAJC27 expression differ between diabetic and non-diabetic individuals?

Research has demonstrated distinct patterns of DNAJC27 expression between diabetic and non-diabetic populations:

In gene expression studies of PBMCs, diabetic individuals showed significantly increased DNAJC27 expression (1.8-fold higher) compared to non-diabetic subjects (P = 0.044) . Similar patterns were observed in adipose tissue, with 1.6-fold higher expression in diabetic individuals (P = 0.048) .

When examining the interaction between obesity and diabetes status:

These findings suggest that obesity may be a stronger driver of DNAJC27 upregulation than diabetes status alone, with the highest expression observed in individuals who present with both conditions.

What is the relationship between DNAJC27 and adipokines in metabolic disease?

DNAJC27 demonstrates significant associations with key adipokines involved in obesity and metabolic dysfunction:

Leptin Relationship:
DNAJC27 shows a strong positive correlation with leptin (r = 0.600, P < 0.0001) . This relationship is particularly noteworthy given leptin's central role in appetite regulation and energy homeostasis. Since leptin is primarily produced by adipocytes and increases proportionally with fat mass, this correlation suggests DNAJC27 may be linked to adipose tissue expansion and dysfunction.

Resistin Relationship:
DNAJC27 is positively associated with resistin levels (r = 0.466, P = 0.002) . Resistin is predominantly expressed in PBMCs, macrophages, and bone marrow in humans and has been implicated in inflammatory processes. This association supports a potential role for DNAJC27 in the inflammatory component of metabolic disorders.

The positive associations of DNAJC27 with both leptin and resistin point to potential pro-inflammatory roles of this protein in obesity and T2D, contrasting with other proteins in the same HSP40 family, such as DNAJB3, which appear to have protective effects .

How does DNAJC27 interact with the MC4R signaling pathway?

Research has identified an important relationship between DNAJC27 and the melanocortin 4 receptor (MC4R) signaling pathway, which is critical for regulating appetite, body weight, and energy homeostasis:

• Genetic Proximity and Association:

  • DNAJC27 is located near the adenylyl cyclase 3 (ADCY3) gene, which has been shown to interact with MC4R .

  • The rs17782313 variant near MC4R is associated with both increased BMI and elevated DNAJC27 levels .

• Functional Impact on MC4R Signaling:

  • Experimental evidence demonstrates that increased levels of DNAJC27 reduce MC4R-mediated formation of cyclic AMP (cAMP) in MC4R ACTOne stable cells .

  • Since MC4R activation normally increases cAMP levels to suppress appetite, the inhibitory effect of DNAJC27 on cAMP formation suggests it may enhance appetite through negative regulation of MC4R signaling.

• Proposed Mechanism:

  • Researchers have proposed that regulation of MC4R activity by DNAJC27 enhances appetite through its effect on cAMP, thereby promoting obesity .

  • This mechanism provides a potential explanation for the genetic associations observed between DNAJC27 variants and increased BMI.

This emerging understanding of DNAJC27's role in MC4R signaling offers new insights into the molecular mechanisms underlying genetic susceptibility to obesity and presents potential targets for therapeutic intervention.

What experimental models are most appropriate for studying DNAJC27 function?

Based on current research approaches, several experimental models have proven valuable for investigating DNAJC27 function:

Cellular Models:

• MC4R ACTOne Stable Cells: These cells have been effectively used to study how DNAJC27 influences MC4R-mediated cAMP formation, providing insights into its role in appetite regulation signaling .

• Primary Human PBMCs: Given the detectable expression of DNAJC27 in PBMCs and the correlation with metabolic parameters, isolated primary PBMCs provide a valuable model for expression studies and cellular function analysis .

Tissue Models:

• Human Adipose Tissue: Adipose tissue samples have been successfully used to examine DNAJC27 expression in the context of obesity and T2D. Both subcutaneous and visceral adipose samples may provide insights into tissue-specific regulation .

Clinical Investigations:

• Case-Control Studies: Comparisons between obese/non-obese and diabetic/non-diabetic human subjects have yielded significant findings regarding DNAJC27 expression and its correlations with metabolic parameters .

• Intervention Studies: Exercise intervention studies have demonstrated that DNAJC27 is downregulated in response to physical activity in obese individuals, suggesting its utility as a biomarker of metabolic improvement .

When designing experiments, researchers should consider the tissue-specific expression patterns of DNAJC27 and its established relationships with metabolic parameters. Multi-tissue analyses are recommended for comprehensive understanding, as DNAJC27 expression in PBMCs, adipose tissue, and circulation shows coordinated regulation.

What genetic variants of DNAJC27 are associated with human metabolic phenotypes?

Genome-wide association studies (GWAS) have identified several key genetic associations between DNAJC27 variants and metabolic traits:

• Association with BMI:

  • GWAS studies in East Asian populations have demonstrated that DNAJC27 loci are associated with increased BMI .

  • Similar associations have been reported in European populations, where DNAJC27 was found to be primarily associated with glucose-related traits and insulin-related phenotypes .

• Proximity to MC4R Variant:

  • The rs17782313 variant near MC4R has been associated with both increased BMI and elevated DNAJC27 levels, suggesting a potential functional relationship between these genetic loci .

  • This association provides a genetic link between DNAJC27 and appetite regulation pathways.

• ADCY3 Proximity:

  • DNAJC27 is located near the adenylyl cyclase 3 (ADCY3) gene, which has been shown to interact with MC4R .

  • This genomic proximity suggests potential co-regulation or functional interactions between these genes in metabolic pathways.

The genetic associations of DNAJC27 with various metabolic traits across different populations highlight its potential importance in the genetic architecture of obesity and related metabolic disorders. These findings provide a genetic basis for the observed correlations between DNAJC27 expression and metabolic parameters.

How can researchers effectively design genetic studies to explore DNAJC27 function?

For researchers planning genetic studies to investigate DNAJC27 function, consider the following methodological approaches:

Study Design Considerations:

• Population Selection:

  • Include diverse ethnic groups, as DNAJC27 associations have been reported in both East Asian and European populations .

  • Stratify populations by both obesity and diabetes status to capture interaction effects, as DNAJC27 expression patterns differ across these subgroups .

• Phenotyping:

  • Collect comprehensive metabolic parameters, including BMI, fasting blood glucose, HOMA-IR, and lipid profiles.

  • Measure adipokines (particularly leptin and resistin) given their strong correlations with DNAJC27 .

• Genomic Approaches:

  • Targeted genotyping of known DNAJC27 variants and neighboring genes (ADCY3, MC4R).

  • Consider whole-exome or whole-genome sequencing to identify rare variants that may have functional impacts.

  • Investigate epigenetic modifications that might regulate DNAJC27 expression in response to environmental factors.

• Functional Validation:

  • Employ CRISPR-Cas9 gene editing to create cellular models with DNAJC27 variants.

  • Develop reporter assays to assess how variants affect DNAJC27 expression or function.

  • Assess cAMP levels and MC4R signaling in the context of different genetic backgrounds.

• Multi-tissue Analysis:

  • Collect both blood and adipose tissue samples when possible, as DNAJC27 shows coordinated expression across these tissues .

  • Consider single-cell RNA sequencing to identify cell-specific expression patterns within heterogeneous tissues.

By implementing these approaches, researchers can more effectively elucidate the genetic basis of DNAJC27 function in metabolic health and disease.

What methodological challenges exist in studying DNAJC27 function?

Researchers investigating DNAJC27 face several technical challenges that require careful consideration:

Expression Analysis Challenges:

• Tissue Heterogeneity: Adipose tissue contains multiple cell types, potentially masking cell-specific changes in DNAJC27 expression. Single-cell approaches may help overcome this limitation.

• Protein Detection: Antibody specificity for DNAJC27 can be challenging, requiring thorough validation of antibodies for Western blotting and immunohistochemistry.

• Post-translational Modifications: These may affect DNAJC27 function but are not captured by standard mRNA expression analyses.

Functional Analysis Challenges:

• Pathway Complexity: DNAJC27 appears to interact with multiple pathways (MC4R signaling, inflammatory processes), necessitating multi-faceted approaches to fully characterize its function.

• Temporal Dynamics: The activity of DNAJC27 may change in response to nutritional status or circadian rhythms, requiring time-course experiments.

• Cellular Localization: Although predicted to localize to the nucleus , confirming the subcellular localization and how it impacts function requires specialized imaging techniques.

Translation to In Vivo Functions:

• Model System Limitations: Appropriate animal models that recapitulate human DNAJC27 function may be challenging to develop.

• Physiological Integration: Understanding how DNAJC27 functions within the complex physiological context of whole-body metabolism requires integrated approaches.

Researchers should address these challenges through complementary techniques and careful experimental design to advance understanding of DNAJC27 function.

How does DNAJC27 expression change in response to interventions?

Understanding how DNAJC27 responds to interventions provides insights into its regulation and potential as a therapeutic target:

Exercise Interventions:
Studies have demonstrated that DNAJC27 is downregulated in obese participants following exercise interventions . This suggests that positive metabolic changes associated with physical activity may be partly mediated through reduction of DNAJC27 levels, consistent with its proposed pro-inflammatory role in metabolic disorders.

Weight Loss:
While direct evidence on the effects of dietary intervention or bariatric surgery on DNAJC27 expression is limited in the provided search results, the consistent association between DNAJC27 and BMI suggests that interventions leading to weight loss may regulate its expression. This represents an important area for future research.

Monitoring Intervention Efficacy:
The positive correlation between circulating DNAJC27 levels and its expression in tissues suggests that plasma DNAJC27 could potentially serve as a biomarker for monitoring the efficacy of metabolic interventions. Longitudinal studies measuring DNAJC27 before and after interventions would be valuable to establish its utility in this context.

Future intervention studies should incorporate measurements of DNAJC27 alongside established metabolic parameters to better understand its regulation and potential as a therapeutic target or biomarker.

What are the most promising areas for future DNAJC27 research?

Several promising research directions could significantly advance our understanding of DNAJC27:

• Mechanistic Studies:

  • Elucidate the precise molecular mechanisms by which DNAJC27 modulates cAMP levels in MC4R signaling .

  • Investigate potential interactions between DNAJC27 and other components of metabolic regulatory pathways, including ADCY3.

  • Determine whether DNAJC27's predicted GTPase activity plays a role in its metabolic functions.

• Translational Research:

  • Develop and validate DNAJC27 as a biomarker for metabolic health, given its strong correlations with established markers like leptin, resistin, and HOMA-IR .

  • Evaluate whether pharmacological targeting of DNAJC27 or its interacting pathways could provide therapeutic benefits for obesity and T2D.

  • Assess whether genetic profiling of DNAJC27 variants could help identify individuals at higher risk for metabolic disorders.

• Tissue-Specific Functions:

  • Explore DNAJC27 function in tissues beyond adipose and PBMCs, particularly in the central nervous system where MC4R signaling plays a crucial role in appetite regulation.

  • Investigate potential tissue-specific regulation of DNAJC27 expression and its implications for metabolic homeostasis.

• Longitudinal Studies:

  • Conduct prospective studies to determine whether elevated DNAJC27 levels precede the development of obesity and T2D, potentially establishing it as a predictive biomarker.

  • Track changes in DNAJC27 throughout disease progression and in response to various interventions.

• Comparative Studies:

  • Investigate the contrasting roles of different HSP40 family members (e.g., DNAJC27 vs. DNAJB3) in metabolic regulation .

  • Explore evolutionary aspects of DNAJC27 function across species to understand conserved metabolic roles.

Addressing these research areas could significantly enhance our understanding of DNAJC27's role in metabolic health and disease, potentially leading to new diagnostic and therapeutic strategies.

How might DNAJC27 research contribute to therapeutic developments for metabolic disorders?

DNAJC27 research offers several promising avenues for therapeutic development in metabolic disorders:

• Target Identification:

  • The inhibitory effect of DNAJC27 on MC4R-mediated cAMP formation suggests that targeting this interaction could potentially enhance MC4R signaling and reduce appetite.

  • Understanding the structural basis of DNAJC27's interaction with the MC4R pathway could facilitate the design of small molecule inhibitors.

• Biomarker Development:

  • The strong correlations between DNAJC27 and established metabolic markers (leptin, resistin, HOMA-IR) suggest it could serve as a biomarker for:

    • Early detection of metabolic dysfunction

    • Monitoring treatment efficacy

    • Stratifying patients for personalized interventions

• Pathway Modulation:

  • The pro-inflammatory associations of DNAJC27 suggest that anti-inflammatory approaches might modulate its effects in metabolic disorders.

  • Exercise-induced downregulation of DNAJC27 indicates that exercise mimetics might achieve similar beneficial effects.

• Genetic Risk Assessment:

  • Identification of DNAJC27 genetic variants associated with metabolic traits could contribute to polygenic risk scores for obesity and T2D.

  • Such genetic information could guide preventive interventions in high-risk individuals.

• Nutritional Interventions:

  • Understanding how nutritional factors regulate DNAJC27 expression could inform dietary recommendations for individuals with specific DNAJC27 variants.

The translational potential of DNAJC27 research is enhanced by its involvement in well-established metabolic pathways, its measurable presence in circulation, and its strong associations with clinically relevant metabolic parameters. Future therapeutic approaches targeting DNAJC27 or its pathways could provide novel strategies for addressing the growing global burden of obesity and T2D.