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Psmd13, a proteosome regulatory subunit for co-transcriptional miR-29a processing during neurogenesis [miRNA-seq]

ABSTRACT: miR-29a plays a critical role in neuronal development and is associated with neurodegenerative diseases, but its regulatory mechanisms remain unclear. To identify genes that influence miR-29a expression, we utilized the genetically diverse Collaborative Cross (CC) mouse strains and conducted expression profiling and Quantitative Trait Loci (QTL) analysis. A significant QTL on chromosome 7 was identified, and ten candidate genes were mapped within this region. RNAi-mediated knockdown experiments revealed that Psmd13 and Nap1l4 significantly increased miR-29a expression, implicating these genes as upstream regulators. Further investigation in mouse neural precursor cells (mNPCs) demonstrated that Psmd13 knockdown enhanced neuronal differentiation, as indicated by increased βIII-tubulin-positive cells, and miR-29a inhibition also promoted this process. Co-immunoprecipitation experiments showed that Psmd13 interacts with Dicer, modulating miR-29a levels through a differentiation-dependent mechanism. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed co-binding of Psmd13 and Dicer at key genomic loci, including miR-29a, influencing chromatin accessibility and transcriptional regulation. Notably, proteasome inhibition using MG132 decreased Psmd13 and Dicer levels, leading to downregulation of miR-29a and impaired neuronal differentiation. These findings suggest that Psmd13 and Dicer coordinate to regulate miR-29a biogenesis and neuronal differentiation, highlighting the proteasome's essential role in maintaining neurodevelopmental homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE287514 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:The miR-29 family is an important player in the molecular pathophysiology of distinct types of cancer, with roles that seems to depend on cellular context. Reduced miR-29 levels are associated with more aggressive disease and its overexpression in cancer and leukemic cell lines inhibits proliferation. In contrast, its overexpression in hematopoietic progenitors, promotes leukemogenesis. We explored the potential roles of miR-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL). As compared to normal T-cells, miR-29a levels are extremely reduced in T-ALL and in the Jurkat cell line. Microarrays analysis in Jurkat cells, following the introduction of synthetic miR-29a mimics, revealed the down-regulation of several predicted targets, including previously described targets (DNMT3a/b, CDK6, PXDN, MCL1, PIK3R1 and CXXC6), and novel targets with roles in active DNA demethylation, such as members of the ten-eleven-translocation (TET) family and TDG. Reduced miR-29a levels contribute to altered epigenetics, as its introduction in Jurkat cells, promotes the demethylation of the AHR gene (commonly methylated in T-ALL). In T-ALL patients, miR-29a levels are significantly associated with blast counts and disease free survival. Our results highlight the relevance of miR-29 in T-ALL physiopathology, and may help to clarify some contrasting findings reported in the literature. In order to identify potential miR-29a targets in T-cell lymphoblastic leukemia, Jurkat cells were electroporated with synthetic RNA molecules corresponding to miR-29a mimics (pre-miR) or inhibitors (anti-miR); and microarray profiles were compared to the profiles of Jurkat cells eletroporated with the corresponding negative controls. Transcripts with levels reduced following the introduction of the pre-miR-29a (as compared to pre-miR-Control), or transcripts acumulated folowing introduction of the anti-miR-29a inhibitor (as compared to anti-miR-Control), were considered potential targets; and were further compared to microRNA target prediction databases. Two paired samples were used for this analysis.

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Psmd13, a proteosome regulatory subunit for co-transcriptional miR-29a processing during neurogenesis [miRNA-seq]

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