Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

Scharler, Cornelia; Poupardin, Rodolphe; Ebner-Peking, Patricia; Wolf, Martin; Schreck, Christina; Brachtl, Gabriele; Andrade, André Cronemberger; Krisch, Linda; Dahéron, Laurence; Schallmoser, Katharina; Jürchott, Karsten; Küchler, Judit; Stachelscheid, Harald; Volk, Hans‐Dieter; Oostendorp, Robert A.J.; Strunk, Dirk

doi:10.1038/s42003-022-04078-1

Cited by 3 publications

(1 citation statement)

References 57 publications

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“…(I) See text. (J) The EOGT (95) - DOCK6 (96) pathway is involved in the regulation of haematopoiesis. (K) On the main network, each position of the pathways (A - H) is indicated by a red square.…”

Section: Resultsmentioning

confidence: 99%

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

Okada,

Oshima,

Maruko

et al. 2024

Preprint

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BACKGROUND: Peripheral inflammation is often associated with depressive disorders, and immunological biomarkers of depression remain a focus of investigation. METHODS: We performed RNA-seq analysis of human peripheral blood mononuclear cell (PBMC) RNA transcripts from a case-control study including subjects with self-reported depression in the pre-symptomatic state of major depressive disorder (MDD), and analysed differential expression of genes (DEGs) and intron retention (IR) using rMats. RESULTS: Among the DEGs with a statistically significant value, both 651 up-regulated and 820 down-regulated genes were enriched in GO (gene ontology) terms of innate and adaptive immunity. The former was particularly enriched in bacterial infection and phagocytosis, while the latter was enriched in genes related to antigen presentation and T cell proliferation and maturation. Genes with the 158 increased and 211 decreased IRs (termed IncIR and DecIR genes, respectively) in the depressed subjects were analysed. Their GO terms were very similar to those of the up- and down-regulated genes, with an emphasis on ciliary assembly and function in the DecIR. The results also showed that a Japanese herbal medicine partially reversed the depression in these subjects after recovering the DecIR and IncIR genes. By imposing the recovered genes on the network of depressed subjects, several new pathways for recovery from depression were successfully discovered. CONCLUSION: Depression was associated with activation of the innate immune response and relative inactivation of T cell signalling. DEGs reflect physiological demands at the transcriptional level, whereas IRs are a mechanism for fine-tuning cytoplasmic homeostasis. Accordingly, IR is a stress response and IR genes are sensors of the physiological state in the cytoplasm. In particular, where ciliary genes were detected by IR analysis, it is expected that there is a defect in ciliary function or immune synaptogenesis in depression. We demonstrate the potential of IR biomarkers in the immunological stratification of depressed patients and their utility in the discovery of novel pathways involved in recovery from depression.

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Section: Resultsmentioning

confidence: 99%

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

Okada,

Oshima,

Maruko

et al. 2024

Preprint

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Challenges and progress related to gene editing in rare skin diseases

Piñón Hofbauer,

Guttmann-Gruber,

Wally

et al. 2024

Advanced Drug Delivery Reviews

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Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

Okada,

Oshima,

Maruko

et al. 2024

Front. Psychiatry

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BackgroundPeripheral inflammation is often associated with depressive disorders, and immunological biomarkers of depression remain a focus of investigation.MethodsWe performed RNA-seq analysis of RNA transcripts of human peripheral blood mononuclear cells from a case-control study including subjects with self-reported depression in the pre-symptomatic state of major depressive disorder and analyzed differentially expressed genes (DEGs) and the frequency of intron retention (IR) using rMATS.ResultsAmong the statistically significant DEGs identified, the 651 upregulated DEGs were particularly enriched in the term “bacterial infection and phagocytosis”, whereas the 820 downregulated DEGs were enriched in the terms “antigen presentation” and “T-cell proliferation and maturation”. We also analyzed 158 genes for which the IR was increased (IncIR) and 211 genes for which the IR was decreased (DecIR) in the depressed subjects. Although the Gene Ontology terms associated with IncIR and DecIR were very similar to those of the up- and downregulated genes, respectively, IR genes appeared to be particularly enriched in genes with sensor functions, with a preponderance of the term “ciliary assembly and function”. The observation that IR genes specifically interact with innate immunity genes suggests that immune-related genes, as well as cilia-related genes, may be excellent markers of depression. Re-analysis of previously published RNA-seq data from patients with MDD showed that common IR genes, particularly our predicted immune- and cilia-related genes, are commonly detected in populations with different levels of depression, providing validity for using IR to detect depression.ConclusionDepression was found to be associated with activation of the innate immune response and relative inactivation of T-cell signaling. The DEGs we identified reflect physiological demands that are controlled at the transcriptional level, whereas the IR results reflect a more direct mechanism for monitoring protein homeostasis. Accordingly, an alteration in IR, namely IncIR or DecIR, is a stress response, and intron-retained transcripts are sensors of the physiological state of the cytoplasm. The results demonstrate the potential of relative IR as a biomarker for the immunological stratification of depressed patients and the utility of IR for the discovery of novel pathways involved in recovery from depression.

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Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

Cited by 3 publications

References 57 publications

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

Challenges and progress related to gene editing in rare skin diseases

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention

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