• IgG antibody
• YTHDF1
• antibody-secreting cells
• lupus
• m6A

• Animals
• Mice
• Immunoglobulin G/immunology
• Immunoglobulin G/metabolism
• Humans
• Homeostasis
• Polyadenylation
• Antibody-Producing Cells/immunology
• RNA, Messenger/metabolism
• RNA, Messenger/genetics
• Adenosine/analogs & derivatives
• Adenosine/metabolism
• Lupus Erythematosus, Systemic/immunology
• Lupus Erythematosus, Systemic/genetics
• Immunoglobulin Heavy Chains/genetics
• Immunoglobulin Heavy Chains/immunology
• RNA-Binding Proteins/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/immunology
• Mice, Inbred C57BL
• Mice, Knockout
• B-Lymphocytes/immunology
• B-Lymphocytes/metabolism
• Disease Models, Animal

• B lymphocyte
• Fatty acid
• Glucose
• Glutamine
• Intermediary metabolism
• Plasma cell
• Signal transduction

• Antibody Formation
• COVID-19
• Humans
• Immunoglobulins/metabolism
• Nutrients
• Plasma Cells
• Signal Transduction

• R01 AI113292 NIAID NIH HHS
• R01 AI149722 NIAID NIH HHS
• R01 HL106812 NHLBI NIH HHS
• R56 AI113292 NIAID NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
• Vanderbilt University Medical Center Institutional Funds (Pathology Microbiology & Immunology Department)

• cancer epigenetics
• cancer genomics
• quantitative trait loci
• myeloma
• genetics research

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/immunology
• Antineoplastic Combined Chemotherapy Protocols
• B-Lymphocytes/immunology
• B-Lymphocytes/pathology
• Base Sequence
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/immunology
• Chromatin/chemistry
• Chromatin/immunology
• Chromosomal Proteins, Non-Histone/genetics
• Chromosomal Proteins, Non-Histone/immunology
• DNA, Intergenic/genetics
• DNA, Intergenic/immunology
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Guanine Nucleotide Exchange Factors/genetics
• Guanine Nucleotide Exchange Factors/immunology
• Humans
• Inheritance Patterns
• Multiple Myeloma/drug therapy
• Multiple Myeloma/genetics
• Multiple Myeloma/immunology
• Multiple Myeloma/pathology
• Neoplasm Proteins/genetics
• Neoplasm Proteins/immunology
• Plasma Cells/immunology
• Plasma Cells/pathology
• Polymorphism, Genetic
• Primary Cell Culture
• Quantitative Trait Loci
• Repressor Proteins/genetics
• Repressor Proteins/immunology
• Risk Assessment
• Transcriptional Elongation Factors/genetics
• Transcriptional Elongation Factors/immunology

• K08 CA252174 NCI NIH HHS
• P01 CA155258 NCI NIH HHS
• R01 HL146500 NHLBI NIH HHS
• K12 CA087723 NCI NIH HHS
• P50 CA100707 NCI NIH HHS
• R01 DK103794 NIDDK NIH HHS
• 17761 Cancer Research UK
• C1298/A8362 Cancer Research UK
• Vetenskapsrådet (Swedish Research Council)
• Cancerfonden (Swedish Cancer Society)
• Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)

The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another.

Interaction between SETD2 and hnRNP L has previously been shown to be implicated in coupling gene transcription and mRNA processing. Here the authors elucidate the molecular basis of this functional interaction, showing that the RRM domain of hnRNP L possesses non-overlapping binding interfaces for engaging RNA and SETD2.

• HNRNP
• MYB
• SP1
• colorectal cancer
• epithelial-mesenchymal transition

• Binding Sites
• Cell Proliferation/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Disease Progression
• Down-Regulation
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Knockout Techniques
• HT29 Cells
• Heterogeneous-Nuclear Ribonucleoproteins/metabolism
• Humans
• Neoplasm Metastasis
• Plicamycin/analogs & derivatives
• Plicamycin/pharmacology
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-myb/genetics
• Proto-Oncogene Proteins c-myb/metabolism
• Sp1 Transcription Factor/antagonists & inhibitors
• Sp1 Transcription Factor/genetics
• Sp1 Transcription Factor/metabolism
• Transcription, Genetic/genetics
• Transfection

• 16K07138 Japan Society for the Promotion of Science
• 20K07581 Japan Society for the Promotion of Science
• 18H02686 Japan Society for the Promotion of Science
• Takeda Science Foundation
• Mochida Memorial Foundation for Medical and Pharmaceutical Research
• Nagono Medical Foundation
• Daiko Foundation
• Princess Takamatsu Cancer Research Fund, Japan
• Japan Society for the Promotion of Science
• Takeda Science Foundation
• Mochida Memorial Foundation for Medical and Pharmaceutical Research

• T cell activation
• alternative polyadenylation
• alternative splicing
• apoptosis

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.

Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.

• B cells
• CD45
• alternative splicing
• hnRNPLL
• immunology
• plasma cells

• Genome-wide association study
• Heritability
• Immunoglobulin G
• N-glycosylation

• Genome-Wide Association Study
• Glycosylation
• Glycosyltransferases/genetics
• Humans
• Immunoglobulin G/genetics
• Immunoglobulin G/metabolism
• Polysaccharides

• MR/R026408/1 Medical Research Council

Antibody secreting cells (ASCs) are terminally differentiated cells of the humoral immune response and must adapt morphologically, transcriptionally, and metabolically to maintain high-rates of antibody (Ab) secretion. ASCs differentiate from activated B cells in lymph nodes and transiently circulate in the blood. Most of the circulating ASCs undergo apoptosis, but a small fraction of early ASCs migrate to the bone marrow (BM) and eventually mature into long-lived plasma cells (LLPCs). LLPC survival is controlled both intrinsically and extrinsically. Their differentiation and maintenance programs are governed by many intrinsic mechanisms involving anti-apoptosis, autophagy, and metabolism. The extrinsic factors involved in LLPC generation include BM stromal cells, cytokines, and chemokines, such as APRIL, IL-6, and CXCL12. In humans, the BM CD19⁻CD38^hiCD138⁺ ASC subset is the main repository of LLPCs, and our recent development of an in vitro BM mimic provides essential tools to study environmental cues that support LLPC survival and the critical molecular mechanisms of maturation from early minted blood ASCs to LLPCs. In this review, we summarize the evidence of LLPC generation and maintenance and provide novel paradigms of LLPC maturation.

• B cell
• antibody-secreting cell
• differentiation
• immunoglobulin
• long-lived plasma cell
• maintenance
• maturation

• EAF2
• ELL2
• polyubiquitination
• prostate cancer

• Androgens/metabolism
• Cell Line, Tumor
• Cell Movement/physiology
• Cell Proliferation/physiology
• Down-Regulation
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Leupeptins/pharmacology
• Male
• Prostatic Neoplasms/enzymology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Protein Stability
• Transcription Factors/metabolism
• Transcriptional Elongation Factors/biosynthesis
• Transcriptional Elongation Factors/genetics
• Transcriptional Elongation Factors/metabolism
• Ubiquitination

• R01 CA186780 NCI NIH HHS
• P50 CA090386 NCI NIH HHS
• R01CA186780 NCI NIH HHS
• R50 CA211242 NCI NIH HHS
• R50CA211242 NCI NIH HHS
• P50CA090386 NCI NIH HHS

Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), an RNA‐binding protein that regulates alternative splicing of pre‐mRNA, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that HNRNPLL promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication‐related genes by HNRNPLL overexpression. Among 13 genes detected in the DNA replication pathway, PCNA,RFC3 and FEN1 showed reproducible upregulation by HNRNPLL overexpression both at mRNA and at protein levels in SW480 and HT29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation‐promoting effect induced by HNRNPLL overexpression. RNA‐immunoprecipitation assay presented a binding of FLAG‐tagged HNRNPLL to mRNA of these genes, and HNRNPLL overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of HNRNPLL in mRNA stability. Finally, analysis of a public RNA sequencing dataset of clinical samples suggested a link between overexpression of HNRNPLL and that of PCNA,RFC3 and FEN1. This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of CDKN1A, which is known to inhibit the cooperative function of PCNA, RFC3 and FEN1, was negatively associated with HNRNPLL expression. These results indicate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and promotes colorectal cancer cell proliferation.

• DNA replication
• HNRNPLL
• cell cycle
• colorectal cancer
• mRNA stability

• COLORECTAL CANCER
• COLORECTAL METASTASES
• MOLECULAR MECHANISMS

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138⁺ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P_combined = 2.5 × 10⁻²⁷; β_combined = −0.24 SD), 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. Our results provide mechanistic insight into MM predisposition.

ELL2 was recently discovered as a susceptibility gene for multiple myeloma (MM). Here, they show that the MM risk allele lowers ELL2 expression in plasma cells, that it also upregulates gene sets related to ribosome biogenesis, and that one of the linked variants reduces binding of MAFF/G/K family transcription factors.

• B cell
• BCL6
• IRF4
• PRDM1
• antibody secretion
• germinal centre
• plasma cell
• regulatory network
• transcription factor

• B-cell
• ELL3
• Lymphoma
• Proliferation
• Transcription elongation

• B-Lymphocytes/immunology
• Cell Division/genetics
• Cell Division/immunology
• Cell Survival/genetics
• Cell Survival/immunology
• DNA Replication/genetics
• DNA Replication/immunology
• Gene Expression Regulation/immunology
• Humans
• Jurkat Cells
• RNA Polymerase II/genetics
• RNA Polymerase II/immunology
• Transcriptional Elongation Factors/genetics
• Transcriptional Elongation Factors/immunology

• P30 CA076292 NCI NIH HHS
• R01 CA164641 NCI NIH HHS
• T32 CA115308 NCI NIH HHS

• RNA binding protein
• RNA processing
• alternative splicing
• immunoglobulin G (IgG)
• lymphocyte
• plasma cells

Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. In this review, we aim to bring the splicing machinery on stage and raise the curtain on its mechanisms and regulation throughout several systems and tissues of the human body, from neurodevelopment to the interactions with the human microbiome. We discuss, on one hand, the essential role of alternative splicing in assuring tissue function, diversity, and swiftness of response in these systems or tissues, and on the other hand, what goes wrong when its regulatory mechanisms fail. We also focus on the possibilities that splicing modulation therapies open for the future of personalized medicine, along with the leading techniques in this field. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.

• Alternative Splice
• Duchenne Muscular Dystrophy
• Round Spermatid
• Spinal Muscular Atrophy
• Splice Factor

• Alternative Splicing
• Humans
• Microbiota
• RNA, Messenger/genetics
• RNA, Messenger/metabolism

• Installation Grant (3057) European Molecular Biology Organization
• Investigador FCT Starting Grant (IF/00595/2014) Fundação para a Ciência e a Tecnologia
• PhD fellowship (PD/BD/105854/2014) Fundação para a Ciência e a Tecnologia
• PhD fellowship (PD/BD/128283/2017) Fundação para a Ciência e a Tecnologia
• Women in Science Program (ERI/NCS/FLP/CDC.13.94) United Nations Educational, Scientific and Cultural Organization
• Innovate Competition Award Fundação AstraZeneca
• IMM/BPD/45-2016,LISBOA-01-0145-FEDER-007391 iMM/FCT/MEC/FEDER
• Start-up funds Instituto de Medicina Molecular

• blimp1
• gene activation and repression
• transcriptional network
• cell adhesion and migration
• immunoglobulin gene control
• chromatin regulation
• epigenetic regulators

• Animals
• B-Lymphocytes/immunology
• B-Lymphocytes/metabolism
• Cell Adhesion/genetics
• Cell Adhesion/immunology
• Cell Differentiation/genetics
• Cell Differentiation/immunology
• Cell Migration Assays, Leukocyte
• Cell Movement/genetics
• Cell Movement/immunology
• Chromatin Immunoprecipitation
• Electrophoretic Mobility Shift Assay
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression Regulation
• HEK293 Cells
• High-Throughput Nucleotide Sequencing
• Humans
• Immunoglobulin Heavy Chains/genetics
• Immunoglobulin Heavy Chains/immunology
• Immunoglobulin kappa-Chains/genetics
• Immunoglobulin kappa-Chains/immunology
• Interferon Regulatory Factors/genetics
• Interferon Regulatory Factors/immunology
• Mass Spectrometry
• Mice
• Plasma Cells/immunology
• Plasma Cells/metabolism
• Positive Regulatory Domain I-Binding Factor 1
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Analysis, DNA
• Sequence Analysis, RNA
• Transcription Factors/genetics
• Transcription Factors/immunology

• 291740 European Research Council
• R01 GM112811 NIGMS NIH HHS

Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, activation and homeostasis, and discuss how defects in splicing can contribute to diseases. We will describe how disruption to trans-acting factors, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), can impact on cell survival and differentiation in the immune system.

• B cells
• T cells
• apoptosis
• hnRNP proteins
• immune tolerance
• pre-mRNA alternative splicing

There is a major transformation in gene expression between mature B cells (including follicular, marginal zone, and germinal center cells) and antibody secreting cells (ASCs), i.e., ASCs, (including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells). This significant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors Prdm1 (B-lymphocyte-induced maturation protein 1), interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of Pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA processing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specific. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA Polymerase II in ASCs to acquire different properties, leading to differences in RNA processing and histone modifications.

• Interferon regulatory factor 4
• Antibody secreting cells
• B cell differentiation
• ELL2
• Secretory-specific antibody
• B-lymphocyte-induced maturation protein 1
• OCA-B
• Super elongation complex
• Xbp-1
• Mammalian target of rapamycin

• PAR-CLIP
• RNA binding proteins
• alternative splicing
• hnRNP
• plasma cells

• RNA sequencing
• alternative polyadenylation
• alternative splicing
• gene expression
• transcriptome
• translation

• ELL2
• HTLV-1
• Human T-cell leukemia virus type 1
• Tax
• Transcription elongation factor

Here, Park et al. used 3D imaging and ChIP-3C techniques to investigate the topographies of the immunoglobulin (Ig) genes and transcripts during B-cell development. The authors show that active Ig genes residing on three different chromosomes colocalize in transcription factories, often near the nuclear periphery. Furthermore, active Ig genes display trans-chromosomal enhancer interactions and frequently share interchromatin trafficking channels. These results reveal tight interconnections between nuclear organization and gene expression during maximal levels of antibody production in plasma cells.

To understand the relationships between nuclear organization and gene expression in a model system, we employed three-dimensional imaging and chromatin immunoprecipitation (ChIP)-chromosome conformation capture (3C) techniques to investigate the topographies of the immunoglobulin (Ig) genes and transcripts during B-cell development. Remarkably, in plasma cells, when antibody synthesis peaks, active Ig genes residing on three different chromosomes exhibit pronounced colocalizations in transcription factories, often near the nuclear periphery, and display trans-chromosomal enhancer interactions, and their transcripts frequently share interchromatin trafficking channels. Conceptually, these features of nuclear organization maximize coordinated transcriptional and transcript trafficking control for potentiating the optimal cytoplasmic assembly of the resulting translation products into protein multimers.

• RNA trafficking
• enhancers
• immunoglobulin genes
• long-range interactions
• nuclear organization
• transcription factories

• immunoglobulin
• antibody secreting cells
• plasma cells
• b-cell differentiation

• Antibodies/pharmacology
• Autophagy/immunology
• B-Cell Maturation Antigen/genetics
• B-Cell Maturation Antigen/immunology
• Cell Differentiation
• Humans
• Immunoglobulin Heavy Chains/biosynthesis
• Immunoglobulin Heavy Chains/genetics
• Lipopolysaccharides/pharmacology
• Lymphocyte Activation/drug effects
• Plasma Cells/cytology
• Plasma Cells/drug effects
• Plasma Cells/immunology
• Plasma Cells/metabolism
• RNA, Messenger/biosynthesis
• RNA, Messenger/genetics
• Receptors, Antigen, B-Cell/genetics
• Receptors, Antigen, B-Cell/immunology
• Receptors, Complement/immunology
• Signal Transduction
• Transcriptional Elongation Factors/genetics
• Transcriptional Elongation Factors/immunology
• Unfolded Protein Response/genetics
• Unfolded Protein Response/immunology

• P30 CA047904 NCI NIH HHS
• P30CA047904 NCI NIH HHS