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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression [ELL2 rescue]

ABSTRACT: To understand the biological mechanism of ELL2 in multiple myeloma (MM), we show that the MM risk allele lowers ELL2 expression in CD138+ plasma cells (Pcombined=2.5×10-27; bcombined=-0.24 s.d.), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111210 | GEO | 2018/04/25

REPOSITORIES: GEO

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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression [ELL2 KO]

Project description:To understand the biological mechanism of ELL2 in multiple myeloma (MM), we show that the MM risk allele lowers ELL2 expression in CD138+ plasma cells (Pcombined=2.5×10-27; bcombined=-0.24 s.d.), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship.

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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression [ELL2 KO]

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Project description:We report RNA-Seq data from MPC11 plasmacytoma cell lines transduced with either control hairpins (shGFP) or hairpins targeting the transcriptional elongation factor ELL2. ELL2 has been identified as regulating the alternative splicing and polyadenylation of immunoglobulin pre-mRNA, and is highly expressed by plasma cells but not other B cells. Notably, ELL2 drives the accumulation of transcripts encoding secreted immunoglobulin at the expense of membrane-associated transcripts. This study sought to examine the impact of ELL2 on mRNA processing at the transcriptome level, and found that ELL2 controls the alternative processing of 12% of annotated transcripts in MPC11 cells. Examination of pre-mRNA splicing patterns in either control or ELL2-depleted cells

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Transcription elongation factor ELL2 influences splicing versus poly(A) site choice in the Ig heavy chain gene

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