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Ago2-Mediated Recruitment of HP1a on Transposable Elements in Drosophila Brain

ABSTRACT: In Drosophila gonads, transposable elements (TEs) are repressed by Piwi-interacting RNA (piRNA) pathway operating both co-transcriptionally and post-transcriptionally. In the non-gonadal tissues, TEs are mainly repressed by short interfering RNA (siRNA) pathway with Argonaute2 (Ago2) as an effector protein. It is generally assumed that this pathway acts at the post-transcriptional level. However, recent data point to its involvement in the co-transcriptional silencing. Here, using DamID, we found drastic decrease of HP1a on TEs (especially on the LTR-containing retrotransposons) and other heterochromatin regions in Ago2-mutant Drosophila brain. HP1a reduction is accompanied by the increased chromatin accessibility of TEs, indicating their derepression. Consistent with these findings, several LTR-containing retrotransposons were up-regulated in larval brain upon Ago2 mutation. Moreover, upon knock-down of lamin Dm0 in neurons, HP1a was increased predominantly on the same set of TEs that have the reduced HP1a binding upon Ago2 mutation. We hypothesize that, since Ago2 was revealed in the common complex with lamin Dm0, the depletion of the latter may release Ago2 in the nucleoplasm, thus enhancing the recruitment of HP1a on TEs. Our findings support the model that TEs in Drosophila brain are partially silenced through Ago2-mediated recruitment of HP1a.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE304397 | GEO | 2025/09/08

REPOSITORIES: GEO

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Project description:The cytoplasmic functions of Wiskott-Aldrich Syndrome family (WASP) proteins are well known and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response and signal transduction. Mis-regulation of these proteins is associated with immune deficiency and metastasis. Cytoplasmic WASP proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex. However, recent evidence has revealed that this classically cytoplasmic protein family also functions in the nucleus. Previously, we identified Drosophila washout (wash) as a new member of the WASP family with essential cytoplasmic roles in early development. Here we show that Wash is also present in the nucleus and plays a key role in nuclear organization via its interaction with Lamin Dm0 at the nuclear envelope. Wash and Lamin Dm0 occupy similar genomic regions that overlap with transcriptionally silent chromatin including constitutive heterochromatin. Strikingly, wash mutant and knockdown nuclei exhibit the same abnormal wrinkled morphology observed in diverse laminopathies, including the Hutchinson-Gilford progeria syndrome, and consistent with disruption of the nuclear organization of several sub-nuclear structures including cajal bodies and the chromocenter in salivary glands. We also found that Wash and Lamin knockdown disrupt chromatin accessibility of repressive compartments in agreement with an observed global redistribution of repressive histone modifications. Functional genetic approaches show wash mutants exhibit similar phenotypes to lamin Dm0 mutants, suggesting they participate in similar regulatory networks. Our results reveal a novel role for Wash in modulating nuclear organization via its interaction with the nuclear envelope protein Lamin Dm0. These findings highlight the functional complexity of WASP family proteins and provide new venues to understand their molecular roles in cell biology and disease. DamID chromatin profiling demostrate that Wash binds similar regions to those bound by Lamin Dm0, in particular transcriptional silent chromatin

Project description:The cytoplasmic functions of Wiskott-Aldrich Syndrome family (WASP) proteins are well known and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response and signal transduction. Mis-regulation of these proteins is associated with immune deficiency and metastasis. Cytoplasmic WASP proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex. However, recent evidence has revealed that this classically cytoplasmic protein family also functions in the nucleus. Previously, we identified Drosophila washout (wash) as a new member of the WASP family with essential cytoplasmic roles in early development. Here we show that Wash is also present in the nucleus and plays a key role in nuclear organization via its interaction with Lamin Dm0 at the nuclear envelope. Wash and Lamin Dm0 occupy similar genomic regions that overlap with transcriptionally silent chromatin including constitutive heterochromatin. Strikingly, wash mutant and knockdown nuclei exhibit the same abnormal wrinkled morphology observed in diverse laminopathies, including the Hutchinson-Gilford progeria syndrome, and consistent with disruption of the nuclear organization of several sub-nuclear structures including cajal bodies and the chromocenter in salivary glands. We also found that Wash and Lamin knockdown disrupt chromatin accessibility of repressive compartments in agreement with an observed global redistribution of repressive histone modifications. Functional genetic approaches show wash mutants exhibit similar phenotypes to lamin Dm0 mutants, suggesting they participate in similar regulatory networks. Our results reveal a novel role for Wash in modulating nuclear organization via its interaction with the nuclear envelope protein Lamin Dm0. These findings highlight the functional complexity of WASP family proteins and provide new venues to understand their molecular roles in cell biology and disease. We evaluated the effect of Wash knockdown in S2R+ cells on chromatin accessibility using an M.SssI-based approach.

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Ago2-Mediated Recruitment of HP1a on Transposable Elements in Drosophila Brain

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