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Chromatin Remodeler Recruitment during Macrophage Differentiation Facilitates Transcription Factor Binding to Enhancers in Mature Cells*

  • Michael J. McAndrew
    Footnotes
    Affiliations
    Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824

    Department of Biochemistry and Molecular Biology
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  • Alison Gjidoda
    Footnotes
    Affiliations
    Department of Biochemistry and Molecular Biology
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  • Mohita Tagore
    Affiliations
    Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824

    Department of Biochemistry and Molecular Biology
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  • Tyler Miksanek
    Affiliations
    Department of Biochemistry and Molecular Biology
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  • Monique Floer
    Correspondence
    To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd., Rm. 410, East Lansing, MI 48824. Tel.: 517-353-3247
    Affiliations
    Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824

    Department of Biochemistry and Molecular Biology
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  • Author Footnotes
    * This work was supported by a Scientist-Development-Grant from the American Heart Association (to M. F.) (13SDG17260004). The authors declare that they have no conflicts of interest with the contents of this article.
    ♦ This article was selected as a Paper of the Week.
    4 M. Floer and A. Gjidoda, unpublished data.
    1 Both authors contributed equally to this work.
Open AccessPublished:July 05, 2016DOI:https://doi.org/10.1074/jbc.M116.734186
      We show how enhancers of macrophage-specific genes are rendered accessible in differentiating macrophages to allow their induction in mature cells in response to an appropriate stimulus. Using a lentiviral knockdown approach in primary differentiating macrophages from mouse bone marrow, we demonstrate that enhancers of Il12b and Il1a are kept relatively lowly occupied by nucleosomes and accessible through recruitment of the nucleosome remodeler BAF/PBAF. Our results using an inducible cell line that expresses an estrogen receptor fusion of the macrophage-specific transcription factor PU.1 (PUER) show that BAF/PBAF recruitment to these enhancers is a consequence of translocation of PUER to the nucleus in the presence of tamoxifen, and we speculate that remodeler recruitment may be directly mediated by PU.1. In the absence of BAF/PBAF recruitment, nucleosome occupancy at the enhancer of Il12b (and to a lesser extent at Il1a) reaches high levels in bone marrow-derived macrophages (BMDMs), and the enhancers are not fully cleared of nucleosomes upon LPS induction, resulting in impaired gene expression. Analysis of Il12b expression in single cells suggests that recruitment of the remodeler is necessary for high levels of transcription from the same promoter, and we propose that remodelers function by increasing nucleosome turnover to facilitate transcription factor over nucleosome binding in a process we have termed “remodeler-assisted competition.”

      Introduction

      Lineage-specific transcription factors (TFs)
      The abbreviations used are:
      TF
      transcription factor
      BMDM
      bone marrow-derived macrophage
      HSPC
      hematopoietic stem and progenitor cell
      KD
      knockdown
      APC
      allophycocyanin
      Bis-Tris
      2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol
      ANOVA
      analysis of variance
      HSD
      honest significant difference
      C/EBPβ
      CCAAT/enhancer-binding protein β.
      play a crucial role in cellular differentiation. These TFs are often pioneer TFs that have been suggested to control access to cis-regulatory elements, in particular gene enhancers, by other ubiquitously expressed TFs (
      • Zaret K.S.
      • Carroll J.S.
      Pioneer transcription factors: establishing competence for gene expression.
      ). The idea that access to regulatory elements is controlled in a cell type-specific manner is supported by the finding that sensitivity of enhancers to nucleases such as DNase I or micrococcal nuclease (MNase) is cell type-specific (for recent studies, see Refs.
      • Mouse ENCODE Consortium
      • Stamatoyannopoulos J.A.
      • Snyder M.
      • Hardison R.
      • Ren B.
      • Gingeras T.
      • Gilbert D.M.
      • Groudine M.
      • Bender M.
      • Kaul R.
      • Canfield T.
      • Giste E.
      • Johnson A.
      • Zhang M.
      • Balasundaram G.
      • Byron R.
      • et al.
      An encyclopedia of mouse DNA elements (Mouse ENCODE).
      and
      • Teif V.B.
      • Vainshtein Y.
      • Caudron-Herger M.
      • Mallm J.P.
      • Marth C.
      • Höfer T.
      • Rippe K.
      Genome-wide nucleosome positioning during embryonic stem cell development.
      ), but how lineage-specific TFs render enhancers accessible during differentiation is unknown. Moreover, what constitutes accessible or “open” chromatin has remained unclear. Although regulatory regions of constitutively expressed genes are often completely nucleosome-free, we recently showed that the enhancers of inducible genes are occupied by intermediate levels of nucleosomes in resting macrophages, and these nucleosomes are evicted when the genes are induced (
      • Gjidoda A.
      • Tagore M.
      • McAndrew M.J.
      • Woods A.
      • Floer M.
      Nucleosomes are stably evicted from enhancers but not promoters upon induction of certain pro-inflammatory genes in mouse macrophages.
      ). Furthermore, before induction, these enhancers are already bound by the macrophage-specific pioneer TF PU.1 and primed for activation as indicated by the presence of certain histone marks (i.e. H3K4me1) (
      • Ghisletti S.
      • Barozzi I.
      • Mietton F.
      • Polletti S.
      • De Santa F.
      • Venturini E.
      • Gregory L.
      • Lonie L.
      • Chew A.
      • Wei C.L.
      • Ragoussis J.
      • Natoli G.
      Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages.
      ). Binding of PU.1 to enhancers was found to lead to a decrease in nucleosome binding (
      • Heinz S.
      • Benner C.
      • Spann N.
      • Bertolino E.
      • Lin Y.C.
      • Laslo P.
      • Cheng J.X.
      • Murre C.
      • Singh H.
      • Glass C.K.
      Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.
      ,
      • Barozzi I.
      • Simonatto M.
      • Bonifacio S.
      • Yang L.
      • Rohs R.
      • Ghisletti S.
      • Natoli G.
      Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers.
      ), and we showed that in the absence of PU.1 binding, macrophage-specific enhancers become associated with the polycomb repressive complex (PRC2) and with highly occupied, H3K27me3-marked nucleosomes as cells differentiate (
      • Tagore M.
      • McAndrew M.J.
      • Gjidoda A.
      • Floer M.
      The lineage-specific transcription factor PU.1 prevents polycomb-mediated heterochromatin formation at macrophage-specific genes.
      ). These results indicated that the pioneer TF PU.1 keeps enhancers accessible and prevents heterochromatin formation at cell type-specific genes, but the underlying mechanism has remained unclear.
      We sought to investigate whether nucleosome remodelers are involved in priming of enhancers. Remodelers of the SWI/SNF family have been shown to facilitate gene expression in many organisms, and SWI/SNF function is best understood in the yeast Saccharomyces cerevisiae, where studies showed that SWI/SNF remodelers remove nucleosomes from promoters or partially unwrap nucleosomes to expose TF binding sites (
      • Bryant G.O.
      • Prabhu V.
      • Floer M.
      • Wang X.
      • Spagna D.
      • Schreiber D.
      • Ptashne M.
      Activator control of nucleosome occupancy in activation and repression of transcription.
      • Reinke H.
      • Hörz W.
      Histones are first hyperacetylated and then lose contact with the activated PHO5 promoter.
      • Floer M.
      • Wang X.
      • Prabhu V.
      • Berrozpe G.
      • Narayan S.
      • Spagna D.
      • Alvarez D.
      • Kendall J.
      • Krasnitz A.
      • Stepansky A.
      • Hicks J.
      • Bryant G.O.
      • Ptashne M.
      A RSC/nucleosome complex determines chromatin architecture and facilitates activator binding.
      • Badis G.
      • Chan E.T.
      • van Bakel H.
      • Pena-Castillo L.
      • Tillo D.
      • Tsui K.
      • Carlson C.D.
      • Gossett A.J.
      • Hasinoff M.J.
      • Warren C.L.
      • Gebbia M.
      • Talukder S.
      • Yang A.
      • Mnaimneh S.
      • Terterov D.
      • et al.
      A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters.
      • Hartley P.D.
      • Madhani H.D.
      Mechanisms that specify promoter nucleosome location and identity.
      ). Mammals have two related SWI/SNF complexes, BAF and PBAF, which share certain subunits but also contain unique subunits that are thought to play a role in recruitment of either complex to specific sites. Both BAF and PBAF use the catalytic subunit BRG1, but BAF can also use the alternate catalytic subunit BRM. BRG1 deletion results in early embryonic lethality, but BRM−/− mice develop normally, and it has been suggested that up-regulation of BRG1 may, in part, compensate for the loss of BRM (
      • Bultman S.
      • Gebuhr T.
      • Yee D.
      • La Mantia C.
      • Nicholson J.
      • Gilliam A.
      • Randazzo F.
      • Metzger D.
      • Chambon P.
      • Crabtree G.
      • Magnuson T.
      A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes.
      ,
      • Reyes J.C.
      • Barra J.
      • Muchardt C.
      • Camus A.
      • Babinet C.
      • Yaniv M.
      Altered control of cellular proliferation in the absence of mammalian brahma (SNF2α).
      ). BRG1 is required for differentiation, including that of lymphoid and myeloid cells, and BRG1 is recruited to cell type-specific genes during differentiation of erythrocytes, suggesting that a BRG1-containing BAF/PBAF complex may prime gene regulatory regions during hematopoiesis (
      • Choi J.
      • Ko M.
      • Jeon S.
      • Jeon Y.
      • Park K.
      • Lee C.
      • Lee H.
      • Seong R.H.
      The SWI/SNF-like BAF complex is essential for early B cell development.
      • Kowenz-Leutz E.
      • Leutz A.
      A C/EBPβ isoform recruits the SWI/SNF complex to activate myeloid genes.
      • Hu G.
      • Schones D.E.
      • Cui K.
      • Ybarra R.
      • Northrup D.
      • Tang Q.
      • Gattinoni L.
      • Restifo N.P.
      • Huang S.
      • Zhao K.
      Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1.
      ). That BAF/PBAF may play a general role in cellular differentiation is further supported by the finding that BRG1 and other BAF/PBAF subunits are frequently mutated in diverse human cancers (
      • Shain A.H.
      • Pollack J.R.
      The spectrum of SWI/SNF mutations, ubiquitous in human cancers.
      ). The core subunit SNF5, for example, is mutated in malignant rhabdoid tumors, a rare aggressive cancer affecting young children, and SNF5 mutation is sufficient to induce such tumors in mice (
      • Klochendler-Yeivin A.
      • Fiette L.
      • Barra J.
      • Muchardt C.
      • Babinet C.
      • Yaniv M.
      The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression.
      ,
      • Roberts C.W.
      • Galusha S.A.
      • McMenamin M.E.
      • Fletcher C.D.
      • Orkin S.H.
      Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice.
      ). Rhabdoid tumor cells are unable to proliferate when BRG1 is inactivated, and it has been suggested that these cells may become dependent on an altered BAF/PBAF complex that still relies on the presence of BRG1 (
      • Wang X.
      • Sansam C.G.
      • Thom C.S.
      • Metzger D.
      • Evans J.A.
      • Nguyen P.T.
      • Roberts C.W.
      Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.
      ). Previous studies showed that BAF/PBAF is required for induction of pro-inflammatory genes in mouse macrophages, because simultaneous knockdown of both BRG1 and BRM impaired induction of a subset of pro-inflammatory genes in a macrophage cell line by bacterial lipopolysaccharides (LPS) (
      • Ramirez-Carrozzi V.R.
      • Braas D.
      • Bhatt D.M.
      • Cheng C.S.
      • Hong C.
      • Doty K.R.
      • Black J.C.
      • Hoffmann A.
      • Carey M.
      • Smale S.T.
      A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling.
      ). These investigators suggested a role for BAF/PBAF in remodeling non-CpG island promoters but did not investigate whether the remodeler creates accessible chromatin at the enhancers of these genes to prime them for later gene induction. These investigators also determined whether primary and secondary response genes show differential dependence on the BAF/PBAF remodelers, and concluded that secondary genes and a subset of primary response genes require the remodeler, whereas other primary response genes are largely independent.
      Here, we show how regulatory regions of two representative macrophage-specific genes (i.e. Il1a, a primary response gen, and Il12b, a secondary response gene) are rendered accessible during differentiation through recruitment of BAF/PBAF, presumably as a consequence of PU.1 binding. This allows induction of these genes in mature macrophages in response to an appropriate signal. We find that both genes depend on BAF/PBAF for induction and nucleosome eviction at their enhancers, but the effects on Il1a are less pronounced. Our analysis of gene expression in single cells suggests that remodelers function by “remodeler-assisted competition” to facilitate TF binding over nucleosome formation at cell type-specific gene enhancers.

      Discussion

      Our results suggest that BAF/PBAF is recruited to macrophage-specific enhancers in response to PUER translocation to the nucleus (Fig. 1), and we speculate that PU.1 recruits the remodeler to these sites. Whether PU.1 directly interacts with BAF/PBAF subunits or whether the interaction is mediated by another factor remains to be determined. We and others showed previously that PU.1 binds to many enhancers together with C/EBPβ, the other macrophage-lineage determining pioneer TF, and C/EBPβ has been shown to directly interact with BAF/PBAF and to mediate its recruitment in other myeloid cells, suggesting that C/EBPβ may recruit BAF/PBAF together with PU.1 in macrophages (
      • Heinz S.
      • Benner C.
      • Spann N.
      • Bertolino E.
      • Lin Y.C.
      • Laslo P.
      • Cheng J.X.
      • Murre C.
      • Singh H.
      • Glass C.K.
      Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.
      ,
      • Tagore M.
      • McAndrew M.J.
      • Gjidoda A.
      • Floer M.
      The lineage-specific transcription factor PU.1 prevents polycomb-mediated heterochromatin formation at macrophage-specific genes.
      ,
      • Kowenz-Leutz E.
      • Leutz A.
      A C/EBPβ isoform recruits the SWI/SNF complex to activate myeloid genes.
      ). The absence of PU.1 and BAF/PBAF at macrophage-specific enhancers in HSPCs suggests that binding of the pioneer TF and recruitment of the remodeler occurs at some time during macrophage differentiation. Whether the presence of the remodeler in turn stabilizes PU.1 binding to enhancers remains to be determined. If BAF/PBAF is already recruited by PU.1 to some extent prior to gene induction in resting macrophages (Fig. 1), how might complete nucleosome eviction be accomplished at enhancers under inducing conditions? We propose that recruited BAF/PBAF increases nucleosome turnover (Fig. 7), so that fractional occupancies of enhancer nucleosomes are about 40–60% in a population of resting BMDMs (Figs. 2 and 5). Upon induction by LPS, signal-induced TFs such as NFκB and AP1 are activated and compete with nucleosomes for binding to their sites in the enhancers. This shifts the equilibrium toward nucleosome removal (0–5%). We call this model remodeler-assisted competition between TFs and nucleosomes for binding to enhancers. In the absence of BAF/PBAF, enhancers become more highly occupied by nucleosomes, which impairs gene expression in mature cells in response to an appropriate stimulus (Figs. 2 and 4). Our model predicts that in the absence of BAF/PBAF, nucleosome turnover is low, and signal-induced TFs and the transcriptional machinery are recruited only infrequently, because nucleosome formation is favored over TF binding. This prediction is borne out by our experiments in single cells, where we found that the fraction of cells expressing Il12b was reduced in the SNF5 KD (Fig. 6, G and H). The model further predicts that in the absence of BAF/PBAF, competing nucleosomes reduce the residence times of signal-induced TFs at enhancers, which in turn may decrease the stability of a transcription complex and therefore the transcriptional output from that promoter. Our findings in single cells support this notion, because we found that the levels of IL12B protein that accumulated in individual cells were higher when BAF/PBAF was present at the Il12b enhancer than in its absence in the SNF5 KD (compare the magnitude of the IL12B-APC signal in Fig. 6E versus Fig. 6H). This finding suggests that in the absence of SNF5, a transcription complex at a promoter may only fire once before it falls apart, whereas in the presence of SNF5, such a complex may be stable for several rounds of transcription. Previous studies at various genes have suggested that enhancers can function either by increasing the probability that a competent transcription complex is formed at a promoter or by increasing the probability that another round of transcription is initiated from the same promoter (for a review, see Ref.
      • Blackwood E.M.
      • Kadonaga J.T.
      Going the distance: a current view of enhancer action.
      ). Our results indicate that the distal enhancer of Il12b may play a role in both initiation and re-initiation and that remodeler-assisted competition facilitates TF over nucleosome binding to the enhancer to stimulate both processes.
      Figure thumbnail gr7
      FIGURE 7Remodeler-assisted competition favors TF over nucleosome binding to sites in enhancers. Our model proposes that recruitment of BAF/PBAF to the distal enhancers of Il12b and Il1a by PU.1 during macrophage differentiation increases turnover of nucleosomes to prevent high occupancy in fully differentiated BMDMs. This results in fractional occupancies of 40–60% for enhancer nucleosomes in the cell population. Under inducing conditions, the equilibrium is shifted toward nucleosome removal as signal-induced TFs (e.g. NFκB and AP1) bind to their sites in the enhancers. Note that increased BAF/PBAF recruitment under inducing conditions (at some enhancers) may further shift the equilibrium toward nucleosome removal. Subsequent steps that result in assembly of a pre-initiation complex at the promoter are not shown.

      Author Contributions

      M. F. conceptualized the study; A. G., M. F., M. J. M., and T. M. developed the methodology; A. G., M. F., and M. J. M. performed validation and formal analysis; A. G., M. F., M. J. M., M. T., and T. M. performed the investigation; M. F. wrote the original draft; M. F. and M. J. M. reviewed and edited the study; M. F. was responsible for supervision, resources, and funding acquisition.

      Note Added in Proof

      The shLuc control data in Fig. 4A were inadvertently duplicated from Fig. 2A in the version of this manuscript that was published as a Paper in Press on July 5, 2016. This error has now been corrected. In addition, the shLuc controls in Fig. 4, C and D, have been removed as they are identical to the data shown in Fig. 2, C and D.

      Acknowledgments

      We thank Amy Ralston for helpful discussions; David Arnosti, Jason Knott, Min-Hao Kuo, and Erik Martinez-Hackert for careful reading of the manuscript; Louis King, Nara Parameswaran, and Michael Steury for help with FACS; and Steve Suhr and John LaPres for help with lentiviral transductions.

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