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Zinc-Finger Protein ZFP318 Is Essential for Expression of Igd, the Alternatively Spliced Igh Product Made by Mature B Lymphocytes

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Zinc-Finger Protein ZFP318 Is Essential for Expression of Igd, the Alternatively Spliced Igh Product Made by Mature B Lymphocytes Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes Anselm Endersa,1, Alanna Shorta, Lisa A. Miosgea, Hannes Bergmanna, Yovina Sontania, Edward M. Bertrama,b, Belinda Whittleb, Bhavani Balakishnanb, Kaoru Yoshidac, Geoff Sjollemab, Matthew A. Fielda, T. Daniel Andrewsa,b, Hiromi Hagiwarac, and Christopher C. Goodnowa,1 aDepartment of Immunology and bAustralian Phenomics Facility, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; and cDepartment of Biomedical Engineering, Toin University of Yokohama, Aoba-ku, Yokohama 225-8503, Japan Contributed by Christopher C. Goodnow, February 13, 2014 (sent for review January 14, 2014) IgD and IgM are produced by alternative splicing of long primary of separate LHV, D, and J elements in pre-B cells. Downstream RNA transcripts from the Ig heavy chain (Igh) locus and serve as from the VDJH exon are six Ighm constant region exons encoding the receptors for antigen on naïve mature B lymphocytes. IgM is the extracellular and transmembrane segments of membrane IgM, made selectively in immature B cells, whereas IgD is coexpressed then five Ighd constant region exons encoding the corresponding with IgM when the cells mature into follicular or marginal zone B segments of IgD, and finally similar sets of Ighg, Ighe,orIgha exons cells, but the transacting factors responsible for this regulated encoding the constant regions of IgG, IgE, and IgA. Isotype change in splicing have remained elusive. Here, we use a genetic switching results from further DNA recombination within the locus screen in mice to identify ZFP318, a nuclear protein with two U1-type that deletes the Ighm and Ighd exons and brings either the Ighg, Ighe Igha ′ VDJ zinc fingers found in RNA-binding proteins and no known role in ,or exons immediately 3 to the H exon, so that the latter is spliced to IgG, IgE, or IgA constant region exons in the the immune system, as a critical factor for IgD expression. A point resulting mRNA (6–8). IgD is the exception, however, because most mutation in an evolutionarily conserved lysine-rich domain B cells do not express IgD by DNA recombination but instead encoded by the alternatively spliced Zfp318 exon 10 abolished via a reversible, developmentally regulated process of alterna- IMMUNOLOGY IgD expression on marginal zone B cells, decreased IgD on follic- tive mRNA splicing of the VDJH exon to the Ighm and Ighd exons ular B cells, and increased IgM, but only slightly decreased the (5, 9, 10). This unique arrangement for coexpression of IgM and percentage of B cells and did not decrease expression of other IgD mRNA by alternative splicing is conserved in bony fish, maturation markers CD21, CD23, or CD62L. A targeted Zfp318 amphibians, reptiles, monotremes, and mammals (11), yet it is not null allele extinguished IgD expression on mature B cells and known how IgD mRNA is selectively produced in mature B cells. increased IgM. Zfp318 mRNA is developmentally regulated in Pre-B cells and immature B cells express very little IgD parallel with IgD, with little in pro-B cells, moderate amounts mRNA and express only IgM, despite transcribing the Ighd exons in immature B cells, and high levels selectively in mature follicu- at levels that are often only two- to threefold lower than the Ighm + − + lar B cells. These findings identify ZFP318 as a crucial factor reg- exons and not differing between IgD and IgD IgM B cells, ulating the expression of the two major antibody isotypes on the when measured by RNA-polymerase run-on experiments in surface of most mature B cells. isolated nuclei (12–16). These results have led to the hypothesis that 25-kb-long Igh pre-mRNA transcripts traverse from the IgHm | IgHd | immunoglobulin isotype | ENU mutation VDJH exon through the Ighd exons in both immature and mature g isotypes with different heavy (H)-chain constant regions are Significance Imade by B lymphocytes in a developmentally regulated series (1). The different antibody isotypes serve as cell surface markers Mammalian B lymphocytes make antibodies of five different of B-cell maturation, as functionally distinct receptors for B-cell heavy chain isotypes, IgM, IgD, IgG, IgE, and IgA. The different activation by antigens and as secreted mediators of different anti- isotypes are produced at discrete stages in B-cell development body effector functions (2). All B cells begin as immature B cells in from a single immunoglobulin heavy chain (Igh) gene, either by bone marrow or fetal liver that express only the IgM isotype on their irreversible rearrangement of the gene to make IgG, IgE, or IgA cell surface (3), comprised of H chains with an N-terminal variable or by alternative splicing of the RNA transcribed from the Igh domain and C-terminal constant region domains, transmem- gene to coexpress IgM and IgD. Developmentally regulated brane segment, and cytoplasmic tail, paired with Ig light chains. trans-acting factors have been hypothesized to control IgM Maturation into follicular B cells, which recirculate among the and IgD expression from large Igh RNAs, but these factors have spleen, lymph nodes, and other secondary lymphoid tissues, is remained elusive for several decades. Here, using a genome- marked by coexpression of a second isotype, IgD. Each mature wide mutation screen in mice, we identify an obscure gene, follicular B cells displays a mixture of cell surface B-cell receptors Zfp318, as encoding a specific and essential factor promoting (BCRs) comprising the same variable domain joined to either IgD IgD expression in mature B cells. or IgM constant regions, with greater levels of IgD than IgM (4, 5). B cells undergo isotype switching after activation by microbial Author contributions: A.E., A.S., L.A.M., H.B., Y.S., E.M.B., B.W., B.B., G.S., M.A.F., T.D.A., and C.C.G. designed research; A.E., A.S., L.A.M., H.B., Y.S., B.W., B.B., G.S., M.A.F., T.D.A., antigens and helper T cells: They irreversibly lose IgM and IgD and and C.C.G. performed research; K.Y. and H.H. contributed new reagents/analytic tools; switch to expressing the same variable domain linked to IgG, IgA, A.E., A.S., L.A.M., H.B., Y.S., E.M.B., B.W., B.B., G.S., M.A.F., T.D.A., and C.C.G. analyzed or IgE constant region domains. Although the process of isotype data; A.E. and C.C.G. wrote the paper. switching to IgG, IgA, and IgE is well understood, the mechanism The authors declare no conflict of interest. for developmentally regulated IgD expression remains obscure. Freely available online through the PNAS open access option. The developmental order of antibody isotype expression is 1To whom correspondence may be addressed. E-mail: [email protected] or reflected in the layout of the Ig heavy chain locus, Igh.Insurface [email protected]. + IgM immature B cells, transcription begins with two variable This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. exons (LH and VDJH) formed by intrachromosomal recombination 1073/pnas.1402739111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1402739111 PNAS Early Edition | 1of6 Downloaded by guest on September 30, 2021 B cells, but an unknown transacting factor alters splicing either by decreased IgD and increased IgM on mature B cells (Fig. 1 A by: (i) promoting RNA cleavage at Ighm polyadenylation sites in and B). Homozygotes had one-third as much IgD as wild-type immature B cells to preclude VDJH splicing to Ighd;or(ii) si- littermates and unrelated controls, whereas heterozygotes had an lencing Ighm cleavage and polyadenylation sites in mature B ∼25% decrease. The frequency of B cells was slightly reduced cells to allow splicing to Ighd (13). In some immature B cells, (Table 1). Exome sequencing of an affected animal followed by failure to express IgD also appears to reflect unloading of genotyping of candidate mutations in a large cohort of siblings RNA Pol II at an attenuation region 3′ to Ighm and 5′ to Ighd, and offspring revealed that the low IgD trait was completely cor- but when this region is removed, there is still little splicing to related with inheritance of a point mutation in the gene encoding IgD (16, 17). In contrast, in terminally differentiated plasma zinc-finger protein (ZFP) 318. cells, transcription termination occurs upstream of Ighd,re- ZFP318 is also called testicular zinc-finger protein (TZF) and sulting in very low expression of Ighd mRNA. has been implicated in transcriptional regulation in testes with Although differential expression of IgM and IgD was one of the genetic deficiency causing infertility in mice (18–21) but has no first examples of developmentally regulated alternative mRNA known function in the immune system. Microarray comparisons splicing, progress to understand its basis has stalled because it has of gene expression in B-cell subsets have identified Zfp318 as not been possible to identify the nature of the transacting factors. a member of a set of mRNAs that increases during maturation of Here, we use a phenotype-driven genetic screen in mice to identify immature B cells into mature follicular B cells (22–24). By ana- a gene that fulfils the criteria for encoding the elusive trans- lyzing flow-sorted B-cell subsets, we confirmed expression of activating factor promoting IgD expression. Zfp318 mRNA closely parallels IgD heavy chain (Ighd) mRNA during B-cell development (Fig. 1C). There was very little Zfp318 Results in pro-B cells in the bone marrow, moderate amounts in imma- + − Identification of a Missense Mutation in Zfp318 Causing Decreased ture (CD93 , CD62L ) B cells in the spleen, and high amounts in − + IgD and Increased IgM.
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