M(odu)LLating the Innate Response
Authors: Ronnie Blecher-Gonen, Ido Amit
Journal: Immunity (2012)

The integration of chromatin modifiers into specific regulatory networks is not fully understood. In this issue of Immunity, Austenaa et al., 2012Austenaa L. Barozzi I. Chronowska A. Termanini A. Ostuni R. Prosperini E. Stewart A.F. Testa G. Natoli G. Immunity. 2012; 36 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar demonstrate a specific role for the histone methyltransferase MLL4 (Wbp7) in controlling the expression of critical molecules in the Toll-like receptor pathway. The integration of chromatin modifiers into specific regulatory networks is not fully understood. In this issue of Immunity, Austenaa et al., 2012Austenaa L. Barozzi I. Chronowska A. Termanini A. Ostuni R. Prosperini E. Stewart A.F. Testa G. Natoli G. Immunity. 2012; 36 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar demonstrate a specific role for the histone methyltransferase MLL4 (Wbp7) in controlling the expression of critical molecules in the Toll-like receptor pathway. The epigenetic code is composed of chemical modifications on histone proteins or DNA, which affect genome output in a sequence-independent manner. These modifications play a critical role in gene regulation and are involved in both normal physiology and disease. Epigenomic modifications can overlay on the DNA sequence long-term "memory" of a particular event or stimuli that the cell has encountered. For example, as cells differentiate they acquire various histone modifications in specific genomic loci, which restrict them to a particular cell lineage. Histone modifying complexes—readers, writers, and erasers—are complexes that bind, add, or remove particular modifications from specific genomic loci. In mammals, H3 histone lysine 4 trimethylation (H3K4me3), a modification localized at the transcription start site of active genes (Li et al., 2007Li B. Carey M. Workman J.L. Cell. 2007; 128: 707-719Abstract Full Text Full Text PDF PubMed Scopus (2677) Google Scholar), is controlled by enzymes of the SET and MLL (mixed lineage leukemia) family. The family includes two SET and four MLL proteins that can create three different complexes with both unique and redundant features. SET and MLL proteins have been associated with a wide variety of diseases—ranging from cancer to mental disorders—but their exact genetic functions are largely unknown. To study the role of MLL4 (the mouse ortholog is named Wbp7) in the innate immune response, Austenaa et al., 2012Austenaa L. Barozzi I. Chronowska A. Termanini A. Ostuni R. Prosperini E. Stewart A.F. Testa G. Natoli G. Immunity. 2012; 36 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar generated Wbp7-deficient macrophages. Using a combined genomic approach, genome-wide measurements of mRNA expression, and chromatin state, they found that in macrophages, Wbp7 is required for robust activation of pathogen-mediated gene response. Surprisingly, whereas Wbp7-depleted macrophages had a severe defect in response to lipopolysacharide (LPS) challenge, the direct effect of Wbp7, presented by genes whose H3K4me3 levels were directly downregulated by Wbp7 depletion, was restricted to a small and very specific subset of genes. One direct target of Wbp7 is Pigp (Figure 1), an essential component of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway (Watanabe et al., 2000Watanabe R. Murakami Y. Marmor M.D. Inoue N. Maeda Y. Hino J. Kangawa K. Julius M. Kinoshita T. EMBO J. 2000; 19: 4402-4411Crossref PubMed Scopus (111) Google Scholar). GPI anchor attachment is a critical mechanism for localizing secreted soluble proteins at the extracellular membrane. Impaired Pigp expression in Wbp7-depleted macrophages abolished GPI anchor-dependent targeting of proteins to the cell membrane. Detection of many pathogens on the extracellular surface is mitigated through a set of molecules known as the Toll-like receptors (TLR). LPS is effectively detected by TLR4 only with its accessory coreceptor CD14, which captures LPS and transfers it to TLR4 (Akashi-Takamura and Miyake, 2008Akashi-Takamura S. Miyake K. Curr. Opin. Immunol. 2008; 20: 420-425Crossref PubMed Scopus (156) Google Scholar). CD14 is localized at the extracellular membrane via a GPI anchor and is mislocalized in Wbp7-depleted macrophages. As a consequence, the response of Wbp7-depleted macrophages to LPS and other bacterial molecules is greatly attenuated (Figure 1). These findings demonstrate how epigenetic changes in one genomic locus can dramatically shape gene expression at other loci and promote a substantial physiological effect in an indirect manner. Memory in the immune system is mostly attributed to the adaptive system, through a dedicated mechanism of DNA-dependent genome rearrangements. This mechanism is critical for generating an appropriate response to pathogens that have been encountered in the history of the organism. The study of Austenaa et al., 2012Austenaa L. Barozzi I. Chronowska A. Termanini A. Ostuni R. Prosperini E. Stewart A.F. Testa G. Natoli G. Immunity. 2012; 36 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar has the potential to lead to an exciting new mechanism, allowing innate immune cells to store memory of past experience through activity of specific chromatin readers, writers, and erasers that paint the epigenomic landscape and control its function in an experience-dependent manner. In macrophages reactivated by two consecutive stimuli of LPS, a particular subset of the stimulus-dependent induced genes is not reactivated in the second pulse of LPS. Genes that are not activated in the second stimuli are mostly enriched for various antibacterial proteins that are toxic for the host in access quantities, and therefore the hyporesponsiveness is a mean of preventing severe tissue damage. Interestingly, the memory mechanism for the nonresponding genes was suggested as addition of trimethyl group on lysine 27 of the H3 histone (H3K27me3), a repressive epigenomic modification attenuating gene expression (Foster et al., 2007Foster S.L. Hargreaves D.C. Medzhitov R. Nature. 2007; 447: 972-978Crossref PubMed Scopus (916) Google Scholar). Because Wbp7 activity is crucial for CD14 proper membrane localization and functionality and because CD14 is an important rheostat for TLR4 activity, a possible memory mechanism of LPS hyporesponsiveness could be Wbp7 inactivation after LPS challenge. This will decrease CD14 expression and TLR4 responsiveness, a hypothesis that requires further investigation in future studies. There are ∼400 chromatin readers, writers, and erasers in the human genome that modify the epigenomic landscape and control gene activation. The results presented here highlight a potential role that individual chromatin modifiers play in modulating the immune response. Specifically, numerous chromatin modifiers may participate in memory of past pathogenic events in various tissues and cells in the host, maintaining memory of past experience though specific epigenomic modifications of various loci responsible for appropriate immune responses. This mechanism was shown for innate immune macrophages but may just as likely happen to coordinate memory in the adaptive immune system, increasing its arching complexity. In the future, a systematic understanding of the regulatory role of all chromatin modifiers in the immune response (Amit et al., 2011Amit I. Regev A. Hacohen N. Nat. Rev. Immunol. 2011; 11: 873-880PubMed Google Scholar) would be of great significance for effective therapeutics. Chromatin readers, writers, and erasers do not contain known sequence recognition motifs and it is mostly unknown how they localize to specific genetic loci. A potential mechanism is recruitment by a combination of different transcription factors (Young, 2011Young R.A. Cell. 2011; 144: 940-954Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar). Recent exciting reports demonstrate a role for large noncoding RNAs (lncRNA) in binding and recruiting chromatin modifiers to site of activity in a mechanism that is not fully understood (Guttman et al., 2011Guttman M. Donaghey J. Carey B.W. Garber M. Grenier J.K. Munson G. Young G. Lucas A.B. Ach R. Bruhn L. et al.Nature. 2011; 477: 295-300Crossref PubMed Scopus (1576) Google Scholar, Wang and Chang, 2011Wang K.C. Chang H.Y. Mol. Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (3250) Google Scholar, Zhao et al., 2008Zhao J. Sun B.K. Erwin J.A. Song J.J. Lee J.T. Science. 2008; 322: 750-756Crossref PubMed Scopus (1272) Google Scholar). These recent studies suggest that lncRNA may be involved together with chromatin complexes in regulating multiple physiological response and malignancies. In this light it would be of great interest to identify Wbp7-associated lncRNAs in macrophages and to study their involvement in localizing Wbp7 to Pigp and other immune response genes. The work of Austenaa et al., 2012Austenaa L. Barozzi I. Chronowska A. Termanini A. Ostuni R. Prosperini E. Stewart A.F. Testa G. Natoli G. Immunity. 2012; 36 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar demonstrates the power of a single chromatin-modifying enzyme in regulating an important physiological process. With no doubt, epigenetic research will continue providing fascinating findings on the machinery of gene regulation in both normal physiology and disease. The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor SynthesisAustenaa et al.ImmunityApril 5, 2012In BriefHistone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1–MLL4) whose specific functions are largely unknown. By using a genomic approach, we found that in macrophages, MLL4 (also known as Wbp7) was required for the expression of Pigp, an essential component of the GPI-GlcNAc transferase, the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. Full-Text PDF Open Archive