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YY1 Plays an Essential Role at All Stages of B-Cell Differentiation

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YY1 Plays an Essential Role at All Stages of B-Cell Differentiation YY1 plays an essential role at all stages of PNAS PLUS B-cell differentiation Eden Kleimana,1, Haiqun Jiaa,1,2, Salvatore Loguerciob,1, Andrew I. Sub, and Ann J. Feeneya,3 aDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; and bDepartment of Molecular Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037 Edited by Max D. Cooper, Emory University, Atlanta, GA, and approved May 16, 2016 (received for review April 25, 2016) Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor single DJ rearrangement to create a maximally diverse antibody shown to be essential for pro–B-cell development. However, the repertoire using the potential germ-line diversity afforded by role of YY1 in other B-cell populations has never been investi- the >100 functional Vh genes. This equal access is accomplished gated. Recent bioinformatics analysis data have implicated YY1 through the process of locus contraction, in which the entire Vh in the germinal center (GC) B-cell transcriptional program. In accord portion of the large 2.8-Mb Igh locus contracts, as determined by with this prediction, we demonstrated that deletion of YY1 by Cγ1- 3D-FISH analyses (14, 15), which results in making the distal Vh Cre completely prevented differentiation of GC B cells and plasma genes equally as close to the DJ rearrangement as the proximal cells. To determine if YY1 was also required for the differentiation Vh genes. Unlike wild-type pro-B cells, YY1-deficient pro-B of other B-cell populations, we deleted YY1 with CD19-Cre and cells do not undergo locus contraction (13). They are also unable to rearrange distal Vh genes, whereas the most proximal two Vh found that all peripheral B-cell subsets, including B1 B cells, require families rearrange at almost normal levels, which may be due to YY1 for their differentiation. Transitional 1 (T1) B cells were the defective locus contraction. When the Igh locus is poised for most dependent upon YY1, being sensitive to even a half-dosage rearrangement, there is noncoding transcription of unrearranged of YY1 and also to short-term YY1 deletion by tamoxifen-induced V and J genes, as well as intergenic antisense transcription. All of Cre. We show that YY1 exerts its effects, in part, by promoting B-cell the V region sense and antisense germ-line transcripts that we − − survival and proliferation. ChIP-sequencing shows that YY1 predom- assayed in that study were found to be greatly reduced in YY1 / inantly binds to promoters, and pathway analysis of the genes that pro-B cells, especially the very prominent antisense transcripts bind YY1 show enrichment in ribosomal functions, mitochondrial within the distal part of the Vh locus at the Pax5-activated INFLAMMATION IMMUNOLOGY AND functions such as bioenergetics, and functions related to transcrip- intergenic repeat (PAIR) elements (16). We have hypothesized tion such as mRNA splicing. By RNA-sequencing analysis of differ- that this noncoding RNA in the Vh locus is at least partially entially expressed genes, we demonstrated that YY1 normally responsible for locus contraction, because we showed by chro- activates genes involved in mitochondrial bioenergetics, whereas mosome conformation capture (3C) that the promoters of the it normally down-regulates genes involved in transcription, mRNA most prominent noncoding RNA within the distal Igh locus, splicing, NF-κB signaling pathways, the AP-1 transcription factor PAIR elements, make direct contact with the region near DJ, network, chromatin remodeling, cytokine signaling pathways, cell presumably within a common transcription factory (16). In ad- adhesion, and cell proliferation. Our results show the crucial role dition, 3D-FISH and 3C demonstrate decreased interaction of that YY1 plays in regulating broad general processes throughout two sites in the middle and distal parts of the Igh locus with Eμ all stages of B-cell differentiation. after YY1 knockdown (17). Therefore, the lack of locus contraction YY1 | B lymphocytes | differentiation | mitochondrial bioenergetics | Significance transcription Ying Yang 1 (YY1) is a ubiquitously expressed transcription ing Yang 1 (YY1) is a ubiquitously expressed zinc finger- factor that has been demonstrated to be essential for pro–B-cell Ycontaining transcription factor that was given its name due development as well as lymphoma. It has recently been pro- to the ability to repress or activate transcription (1). YY1 was posed that YY1 regulates the germinal center B-cell transcrip- first identified in 1991 as being a key regulator for several viral tional program. We confirm this hypothesis and additionally genes, as well as a repressor of the Ig 3′κ-enhancer (1–5). YY1 show that YY1 is equally essential for all stages of B-cell differ- can activate or repress genes by recruiting a variety of coactivators entiation. Through ChIP-sequencing analysis of YY1 binding, and or corepressors. It can recruit several histone-modifying com- analysis of differentially expressed genes from RNA-sequencing, plexes, including those containing histone acetyltransferases or our data show that, in addition to the regulation of several histone deacetylases, thus resulting in opposing epigenetic profiles B-cell–specific genes, YY1 regulates many genes and pathways (6, 7). It is highly conserved from Xenopus to humans, and there is important in basic cellular functions, such as mitochondrial bio- even a Drosophila ortholog of YY1. YY1 has also been implicated energetics, transcription, ribosomal function, and cellular pro- in Polycomb-mediated repression (8), and it has strong homology liferation, thus explaining the requirement for YY1 at all stages to Pho, the DNA binding recruiter of Polycomb-repressive com- of B-cell differentiation. plexes in Drosophila (9, 10). Pho also plays an important role in embryonic patterning in Drosophila.InXenopus, YY1 also is im- Author contributions: E.K., H.J., and A.J.F. designed research; E.K. and H.J. performed research; E.K., H.J., S.L., A.I.S., and A.J.F. analyzed data; and E.K. and A.J.F. wrote portant in patterning and neural induction (11). Not surprisingly the paper. therefore, germ-line deletion of YY1 leads to embryonic lethality The authors declare no conflict of interest. at the periimplantation stage (12). Within the B lineage of lymphocytes, YY1 was shown to play This article is a PNAS Direct Submission. critical roles at the pro–B-cell stage of differentiation. Condi- Data deposition: The data reported in this paper have been deposited in the Gene Ex- tional deletion of YY1 with mb1-Cre resulted in a block at the pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE73534). pro–B-cell to pre–B-cell stage (13). In pro-B cells, the Igh locus 1E.K., H.J., and S.L. contributed equally to this work. undergoes V(D)J rearrangement. D-to-J gene rearrangement 2Present address: California Institute for Biomedical Research (Calibr), La Jolla, CA 92037. occurs first on both alleles, followed by V-to-DJ rearrangement 3To whom correspondence should be addressed. Email: [email protected]. on one allele. Because only one V-to-DJ rearrangement is allowed This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. on each allele, all V genes should have equivalent access to the 1073/pnas.1606297113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1606297113 PNAS | Published online June 22, 2016 | E3911–E3920 Downloaded by guest on September 25, 2021 transcriptional signatures of genes specific for each stage of nor- mal B-cell differentiation (19). The bioinformatic analysis of the signature genes for each stage showed that only the GC B-cell signature genes had a significant enrichment for YY1 binding motifs, and thus the authors concluded that YY1 was a regulator of the GC B-cell–specific transcriptional program. Furthermore, using an in vitro class switch culture system, it has been demon- strated that YY1 interacts with activation-induced cytidine de- aminase (AID) and increases AID nuclear stability (20). AID is activated in GC B cells to carry out SHM and CSR, thus providing an additional potential role for YY1 during in vivo GC B-cell development. If YY1 were indeed a critical regulator of GC B-cell dif- ferentiation, then we predicted that a GC-specific deletion of YY1 should ablate the ability of naive B cells to become GC Fig. 1. YY1 deletion prevents the differentiation of naive B cells into GC B + f/f × γ B cells. Here, we present data showing that conditional de- cells, PCs, and IgG1 isotype-switched cells. YY1 C 1-Cre mice were im- letion of YY1 in B cells with Cγ1-Cre within 2 d after anti- munized with OVA/LPS/alum. Splenic B-cell populations from immunized gen activation does indeed prevent the appearance of GC mice and unimmunized controls were analyzed by flow cytometry 8 d after immunization. YY1 deletion prevented the differentiation of naive B cells B cells after antigen stimulation. To determine if YY1 was + into GC B cells (A), PCs (B), and IgG1 B cells (C). Values from individual mice only critical for the differentiation of GC B cells, we analyzed are displayed, and they are derived from a total of four experiments. ***P < mice in which YY1 was deleted by CD19-Cre, which deletes 0.0001. NS, not significant. in the late BM stage. These mice showed that, unlike the prediction based on the bioinformatic analysis of B-signature genes, YY1 is required for every stage of B-cell maturation. and lack of rearrangement of distal Vh genes in YY1-deficient Analysis of genes that bound YY1 in ChIP-sequencing (ChIP- pro-B cells may be due, in part, to a lack of noncoding antisense seq) at four stages of differentiation and comparison of the RNA in the distal part of the Vh region and to a lack of YY1- RNA-sequencing (RNA-seq) gene expression profile of pro- dependent long-range interactions.
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