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Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

ABSTRACT: 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.

SUBMITTER: Mr. Poorani, Ganesh Subramani

PROVIDER: S-SCDT-10_1038-S44319-024-00152-3 | biostudies-other |

REPOSITORIES: biostudies-other

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Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

Project description: Not available

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Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

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

Evolutionarily Conserved Alternative Splicing Across Monocots.

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Alternative splicing of ALCAM enables tunable regulation of cell-cell adhesion through differential proteolysis.

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Epigenetic features are significantly associated with alternative splicing.

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