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DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [eCLIP-seq]

ABSTRACT: Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5′ untranslated regions (5′UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at mid-gestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female-differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5′ UTRs and requires DDX3X. These findings uncover a sex-specific post-transcriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.

ORGANISM(S): Mus musculus

PROVIDER: GSE318097 | GEO | 2026/04/27

REPOSITORIES: GEO

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DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [Ribo-Seq]

Project description:Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5′ untranslated regions (5′UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at mid-gestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female-differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5′ UTRs and requires DDX3X. These findings uncover a sex-specific post-transcriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.

2026-04-27 | GSE318098 | GEO

DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [RNA-Seq]

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Sex specific pertubations of neuronal development caused by mutations in the autism risk gene DDX3X

Project description:DDX3X is an X-linked RNA helicase that escapes X chromosome inactivation and is expressed at higher levels in female brains. Mutations in DDX3X are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and are predominantly identified in females. Using cellular and mouse models, we show that Ddx3x mediates sexual dimorphisms in brain development at a molecular, cellular, and behavioral level. During cortical neuronal development, Ddx3x sustains a female-biased signature of enhanced ribosomal biogenesis and mRNA metabolism. Compared to male neurons, female neurons display larger nucleoli, higher expression of a set of ribosomal proteins, and a higher cytoplasm-to-nucleus ratio of ribosomal RNA. All these sex dimorphisms are obliterated by Ddx3x loss. Ddx3x regulates dendritic arborization complexity in a sex- and dose-dependent manner in both female and male neurons. Ddx3x regulates the development of dendritic spines but only in female neurons. Further, ablating Ddx3x conditionally in forebrain neurons is sufficient to yield sex-specific changes in developmental outcomes and motor function. Together, these findings pose Ddx3x as a mediator of sexual differentiation during neurodevelopment and open new avenues to understand sex differences in health and disease.

2025-05-26 | PXD060033 | Pride

Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate hollow condensates of DDX3X disease variants

Project description:The sex chromosome-encoded RNA helicases DDX3X and DDX3Y play important roles in RNA metabolism. Heterozygous mutations of DDX3X frequently occur in cancers and neurodevelopmental disorders which have strong sex biases. However, how different DDX3X variants impair cellular function in sex specific genetic background is not understood. Herein, we found that DDX3X variants with significantly impaired ATPase activities demixed into the shells of unique hollow condensates, the dynamics of which were further differentiated by the RNA binding affinities of the different DDX3X variants. Proteomic and imaging studies revealed that DDX3X variant condensates sequestered wild-type DDX3X, DDX3Y, and other proteins important for various signaling pathways. Intriguingly, wild-type DDX3X improved the dynamics of heterogenous variant/wild-type hollow condensates more than DDX3Y. These results suggest that DDX3X variants with distinct enzymatic and condensation propensities may interact uniquely with wild-type DDX3X or DDX3Y to cause sex-specific cellular impacts.

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DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [RNA-Seq]

Project description:DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [RNA-Seq]

| PRJNA1416455 | ENA

DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [eCLIP-seq]

Project description:DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [eCLIP-seq]

| PRJNA1416456 | ENA

DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [Ribo-Seq]

Project description:DDX3X-Mediated Translation of Structured Cardiac mRNAs is Essential for Female Heart Development [Ribo-Seq]

| PRJNA1416463 | ENA

APEX-seq performed for DDX3X and DDX3Y without arsenite treatment

Project description:Sex differences are pervasive in human health and disease. One of the major keys to sex-biased differences lies in the sex chromosomes, which encode a group of sex-specific protein homologs. Although the functions of the X chromosome proteins are well appreciated, how they compare with their Y chromosome homologs remains elusive. One pair of sex chromosome-encoded proteins are the RNA helicases DDX3X and DDX3Y. DDX3X and DDX3Y can both form stress granules (SGs) under different types of stress. SGs are composed of a stable core structure, they are surrounded by a dynamic shell with assembly, disassembly, and transitions of proteins and RNA between the core and shell. Different SGs have distinct proteins and RNA constituents, which raises the possibility that different SGs might perform different biological functions. Previously, we performed APEX-seq to explore the RNA compositions in DDX3X and DDX3Y SGs, however, the difference between the mRNA partner of DDX3X and DDX3Y without stress treatment is still uncharted. Therefore, we applied the APEX-seq to cytosome diffused DDX3X and DDX3Y.

2022-06-01 | GSE193783 | GEO

Impaired cortical development and translational control in a missense mouse model of DDX3X syndrome

Project description:Heterozygous mutations in the X-linked RNA helicase DDX3X cause DDX3X syndrome, a rare neurodevelopmental disorder associated with cortical malformation and autism. Amongst the ~200 known de novo DDX3X variants, half are missense while the others are predicted loss-of-function (LoF). LoF mouse models reveal DDX3X loss impairs progenitors’ ability to generate excitatory neurons. Yet, how missense mutations impact corticogenesis in vivo is unknown. Here, we generated a conditional mouse model of Ddx3xT532M, a clinically severe and recurrent DDX3X syndrome mutation found in females. Using Cre-mediated expression of Ddx3xT532M in cortical progenitors and their progeny, we show this mutation alters corticogenesis and translation. Ddx3xT532M conditional knock-in (KI) males have severe microcephaly and apoptosis. In contrast, Ddx3xT532M conditional heterozygous (cHet) females exhibit only mild reductions in cortical size and neurogenesis. Using polysome fractionation of Ddx3xT532M and Ddx3xLoF cHet female cortices, we discover that Ddx3xT532M affects translation of key targets, with qualitative differences from Ddx3xLoF cHet females. Collectively, these cellular and molecular findings suggest that, the clinically severe Ddx3xT532M variant in cHet females is phenotypically similar to, but molecularly distinct from, Ddx3x haploinsufficiency in corticogenesis. Our study establishes a new model for understanding how missense mutations may cause DDX3X syndrome.

2025-11-17 | GSE296911 | GEO

DDX3X regulation of global translation is impaired by medulloblastoma-associated mutations [RiboSeq]

Project description:Whole-genome sequencing recently identified recurrent missense mutations in the RNA helicase DDX3X in pediatric medulloblastoma (MB) and other tumors. The normal function of DDX3X is poorly understood, and the consequences of its cancer-associated mutations have not been explored. Here we used genomic, biochemical, cell biological, and animal modeling approaches to investigate normal DDX3X function and the impact of cancer-associated DDX3X mutations. Cross-linking immunoprecipitation–high-throughput sequencing (CLIPseq) analyses revealed that DDX3X binds primarily to ~1000 mature mRNA targets at binding sites spanning the full mRNA length; their enrichment in the coding regions suggests that DDX3X plays a role in translational elongation. The association of wild-type DDX3X with polysomes is consistent with this observation. Cancer-associated mutations result in loss of DDX3X from polysomes and accumulation of mutant DDX3X in stress granules (cytoplasmic accumulations of translationally arrested mRNAs). Mutation-dependent redistribution of DDX3X to stress granules is also observed in a Drosophila model system and in MB tumor cells from patients carrying DDX3X mutations. Importantly, mRNAs targeted by DDX3X are enriched in translation factors, suggesting that DDX3X regulates translation both directly and indirectly. Indeed, depletion of DDX3X by RNAi or over-expression of mutant DDX3X significantly impairs global protein synthesis. Ribosome profiling confirmed this observation and showed a 5’ bias in ribosomal occupancy, further confirming the role of DDX3X in translational elongation. Together, our data show that DDX3X is a key regulator of translation and that this function is impaired by cancer-associated mutations. Finally, we found that medulloblastoma-related mutant DDX3X can efficiently bind the wild-type form suggesting that mutant DDX3X could exert a dominant negative effect in vivo.

2016-05-20 | GSE59095 | GEO

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