Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation
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ABSTRACT:
PROVIDER: PRJNA1011292 | ENA |
REPOSITORIES: ENA
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Project description:The multifunctional RNA-binding protein hnRNPL has been implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, and thereby germinal center and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. The comparative analysis of RNA-seq data from B cells and another 8 hnRNPL-depleted cell types reveals a common function in the Myc and E2F transcriptional programs required for proliferation, likely borne out of a large alternative splicing change affecting multiple transcription regulators. Notably, while individual gene expression changes were cell type specific, several alternative splicing events affecting histone modifiers like SIRT1, KDM6A, and NSD2, were conserved across cell types, which could contribute to gene expression changes upon hnRNPL loss. SIRT1 reduction due to alternative splicing, and other transcriptional changes suggested mitochondrial defects in hnRNPL-deficient B cells. We confirmed dysfunctional mitochondria and ROS overproduction, which could explain the B cell activation defect. Thus, hnRNPL is essential for the resting to activated B cell transition by regulating transcriptional programs, most likely by splicing regulation affecting several histone modifiers.
2024-04-24 | GSE242069 | GEO
Project description: Not available
| S-BSST1365 | biostudies-other
Project description:The multifunctional RNA-binding protein hnRNPL is implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, and germinal center and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. Comparative analysis of RNA-seq data from activated B cells and further eight hnRNPL-depleted cell types reveals common effects on MYC and E2F transcriptional programs required for proliferation. Notably, while individual gene expression changes are cell type specific, several alternative splicing events affecting histone modifiers like KDM6A and SIRT1, are conserved across cell types. Moreover, hnRNPL-deficient B cells show global changes in H3K27me3 and H3K9ac. Epigenetic dysregulation after hnRNPL loss could underlie differential gene expression and upregulation of lncRNAs, and explain common and cell type-specific phenotypes, such as dysfunctional mitochondria and ROS overproduction in mouse B cells. Thus, hnRNPL is essential for the resting-to-activated B cell transition by regulating transcriptional programs and metabolism, at least in part through the alternative splicing of several histone modifiers.
| S-SCDT-10_1038-S44319-024-00152-3 | biostudies-other
Project description:In the current project with aim to unequivocally characterize a novel splicing-regulatory network that proves to be a central mediator of endothelial barrier function and vascular integrity. At the core of this network is the endothelial enriched lncRNA NTRAS (annotated as RP11-354k1.1) is shown to control alternative splicing decisions in HUVECs through interplaying with splicing factor hnRNPL. Specifically, in the project we show that NTRAS sequesters the splicing factor hnRNPL through a CA dinucleotide motif, to enhance TJP1 exon 20 usage, thereby TJP1α+ isoform. In turn disrupting TJP1α+ isoform expression impaired endothelial barrier function. Collectively, this splicing-regulatory network might prove fundamental in unlocking new interventions strategic to prevent or reverse vascular leakage.
2022-01-10 | E-MTAB-11311 | biostudies-arrayexpress
Project description:RNA immunoprecipitation coupled with next generation sequencing (RIP-seq) was used to map the HNRNPL-RNA interactome in LNCaP cells.
2016-12-28 | GSE72841 | GEO
Project description:HNRNPL plays a critical role in regulating epidermal stem and progenitor cell function through regulating integrin gene expression at transcriptional level.
2021-09-21 | GSE162546 | GEO
Project description:NTRAS hnRNPL RNA sequencing in HUVECs
| PRJEB49865 | ENA
Project description:Evidence of widespread transcription at active enhancers became apparent. However, our understanding about the functions of enhancer RNAs (eRNAs) and their mechanistic roles remains incomplete. Here, we study eRNA regulation and function using skeletal myoblast differentiation as a paradigm. We provide a panoramic view of enhancer transcription and uncover reprogramming in enhancer transcription occurring during myogenic differentiation. We demonstrate the critical role of MyoD in activating eRNAs production. Results from in depth dissection of two eRNAs transcribed from super enhancers (seRNA-1 and -2) suggest that seRNAs can promote myogenic differentiation in vitro and in vivo; the induction of the seRNAs is in coordination with the activation of the neighboring genes and seRNA loss largely impairs their expression. Mechanistically, we elucidate these seRNAs specifically bind to heterogeneous nuclear ribonucleoprotein L (hnRNPL) and modulate hnRNPL binding to the target promoter. A CAAA tract on the seRNA was identified to be essential in mediating the interaction between seRNA-1 and hnRNPL. Disruption of seRNA-hnRNPL interaction attenuates Pol II and H3K36me3 deposition at the target genes, in coincidence with the reduction of their expression. Furthermore, analyses of hnRNPL binding transcriptome-wide reveals its association with eRNAs is a general phenomenon in multiple cells. Collectively, we propose that eRNA-hnRNPL interaction contributes to target mRNA activation.
2019-10-03 | GSE114659 | GEO
Project description:Evidence of widespread transcription at active enhancers became apparent. However, our understanding about the functions of enhancer RNAs (eRNAs) and their mechanistic roles remains incomplete. Here, we study eRNA regulation and function using skeletal myoblast differentiation as a paradigm. We provide a panoramic view of enhancer transcription and uncover reprogramming in enhancer transcription occurring during myogenic differentiation. We demonstrate the critical role of MyoD in activating eRNAs production. Results from in depth dissection of two eRNAs transcribed from super enhancers (seRNA-1 and -2) suggest that seRNAs can promote myogenic differentiation in vitro and in vivo; the induction of the seRNAs is in coordination with the activation of the neighboring genes and seRNA loss largely impairs their expression. Mechanistically, we elucidate these seRNAs specifically bind to heterogeneous nuclear ribonucleoprotein L (hnRNPL) and modulate hnRNPL binding to the target promoter. A CAAA tract on the seRNA was identified to be essential in mediating the interaction between seRNA-1 and hnRNPL. Disruption of seRNA-hnRNPL interaction attenuates Pol II and H3K36me3 deposition at the target genes, in coincidence with the reduction of their expression. Furthermore, analyses of hnRNPL binding transcriptome-wide reveals its association with eRNAs is a general phenomenon in multiple cells. Collectively, we propose that eRNA-hnRNPL interaction contributes to target mRNA activation.
2019-10-03 | GSE114658 | GEO
Project description:Evidence of widespread transcription at active enhancers became apparent. However, our understanding about the functions of enhancer RNAs (eRNAs) and their mechanistic roles remains incomplete. Here, we study eRNA regulation and function using skeletal myoblast differentiation as a paradigm. We provide a panoramic view of enhancer transcription and uncover reprogramming in enhancer transcription occurring during myogenic differentiation. We demonstrate the critical role of MyoD in activating eRNAs production. Results from in depth dissection of two eRNAs transcribed from super enhancers (seRNA-1 and -2) suggest that seRNAs can promote myogenic differentiation in vitro and in vivo; the induction of the seRNAs is in coordination with the activation of the neighboring genes and seRNA loss largely impairs their expression. Mechanistically, we elucidate these seRNAs specifically bind to heterogeneous nuclear ribonucleoprotein L (hnRNPL) and modulate hnRNPL binding to the target promoter. A CAAA tract on the seRNA was identified to be essential in mediating the interaction between seRNA-1 and hnRNPL. Disruption of seRNA-hnRNPL interaction attenuates Pol II and H3K36me3 deposition at the target genes, in coincidence with the reduction of their expression. Furthermore, analyses of hnRNPL binding transcriptome-wide reveals its association with eRNAs is a general phenomenon in multiple cells. Collectively, we propose that eRNA-hnRNPL interaction contributes to target mRNA activation.
2019-10-03 | GSE114657 | GEO