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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.

2018-04-25 | GSE111199 | GEO

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

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

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

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RNA-Seq of control and ELL2-depleted MPC11 plasmacytoma cell lines

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

2012-09-07 | E-GEOD-40285 | biostudies-arrayexpress

RNA-Seq of control and ELL2-depleted MPC11 plasmacytoma cell lines

2012-09-07 | GSE40285 | GEO

Determining ELL2 direct targets via ChIPseq

Project description:A plasma cell line was used to determine which genes have ELL2 protein bound to them.

2018-05-15 | GSE114435 | GEO

Transcription profiling of mouse B cells transfected with ELL2 vs. controls reveals transcription elongation factor ELL2 influences splicing versus poly(A) site choice in the Ig heavy chain gene

Project description:Processing of Immunoglobulin heavy chain (IgH) mRNA is a paradigm for competition between splicing and polyadenylation. In plasma cells pre-mRNA is polyadenylated mainly at the promoter-proximal secretory site while B-cells utilize a cryptic 5â?? splice site in the last secretory-specific exon; these are mutually exclusive events for all IgH pre-mRNAs. Transcription elongation factor ELL2, more abundant in plasma cells relative to B-cells, was down-modulated by overexpression of heterogenous ribonucleoprotein F, a condition which reduced production of secretory IgH mRNA. Transfection of B-cells with ELL2 and the IgH reporter showed an accelerated use of the secretory poly(A) site, positioned in competition with the splice to M1; a small interfering RNA to ELL2 reduced expression of IgH secretory mRNA. Co-transcription factors ELL1 and PC4 were ineffective at driving secretory-poly(A) site use. ELL2 had little effect on poly(A) site choice with reporters containing tandem-linked poly(A) sites. Shorter forms of ELL2 protein result from both internal initiation at M186 and protein processing. An alternative splicing reporter driven by IgH or non-Ig promoters revealed that ELL2 and its M186 initiated form were able to accelerate exon skipping. Therefore, ELL2 influences IgH pre-mRNA processing through facilitating skipping of the alternative splice to the membrane form. Experiment Overall Design: AxJ plasma cells were stably transfected to overexpress hnRNP-F, -H or empty vector. Clones showing high overexpression levels of F or H by western blot were selected. The IgH sec to mb ratios of these clones were determined. A global gene expression analysis was performed on mRNA from two clones from hnRNP-F, which demonstrated a lower sec:mb ratio, and one from each of the controls: overexpression of hnRNP-H, or transfection with empty vector, or A20 B-cells, using Affymetrix gene micro array technology.

2008-06-18 | E-GEOD-11586 | biostudies-arrayexpress

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

Project description:Processing of Immunoglobulin heavy chain (IgH) mRNA is a paradigm for competition between splicing and polyadenylation. In plasma cells pre-mRNA is polyadenylated mainly at the promoter-proximal secretory site while B-cells utilize a cryptic 5’ splice site in the last secretory-specific exon; these are mutually exclusive events for all IgH pre-mRNAs. Transcription elongation factor ELL2, more abundant in plasma cells relative to B-cells, was down-modulated by overexpression of heterogenous ribonucleoprotein F, a condition which reduced production of secretory IgH mRNA. Transfection of B-cells with ELL2 and the IgH reporter showed an accelerated use of the secretory poly(A) site, positioned in competition with the splice to M1; a small interfering RNA to ELL2 reduced expression of IgH secretory mRNA. Co-transcription factors ELL1 and PC4 were ineffective at driving secretory-poly(A) site use. ELL2 had little effect on poly(A) site choice with reporters containing tandem-linked poly(A) sites. Shorter forms of ELL2 protein result from both internal initiation at M186 and protein processing. An alternative splicing reporter driven by IgH or non-Ig promoters revealed that ELL2 and its M186 initiated form were able to accelerate exon skipping. Therefore, ELL2 influences IgH pre-mRNA processing through facilitating skipping of the alternative splice to the membrane form.

2008-06-01 | GSE11586 | GEO

Determining ELL2 direct targets via ChIPseq

Project description:Determining ELL2 direct targets via ChIPseq

| PRJNA471339 | ENA