Structure of human <scp>S</scp>p140 <scp>PHD</scp> finger: an atypical fold interacting with <scp>P</scp>in1

Zucchelli, Chiara; Tamburri, Simone; Quilici, Giacomo; Palagano, Eleonora; Berardi, Andrea; Saare, Mario; Peterson, Pärt; Bachi, Ángela; Musco, Giovanna

doi:10.1111/febs.12588

Cited by 17 publications

(10 citation statements)

References 64 publications

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“…Such a domain organization is similar to the cases of TRIM24 and TRIM33 but different from that of BPTF and other independently folded PHD fingers (22,(35)(36)(37). The requirement of an adjacent bromodomain for functional PHD finger folding may explain why the Sp140 PHD finger alone did not display clear histone H3K4me0 binding activity in the previous report (13).…”

Section: Discussionmentioning

confidence: 61%

“…Despite this, it was reported in a previous study that the PHD finger of Sp140 did not harbor the histone binding activity (13), which raised concerns as to whether the PHD fingers of Sp100 family members were indeed histone readers or not. Here we demonstrate that PHD fingers of both Sp100C and Sp140 display unmethylated histone H3K4 reader activity with single digit micromolar level binding affinity.…”

Section: Discussionmentioning

confidence: 89%

“…Sp140, a lymphocyte-specific Sp100C homolog that harbors a similar PHD-Bromo cassette, is a risk factor in chronic lymphocytic leukemia and may serve as a transcriptional co-activator (9 -12 of the Sp140 PHD finger was not detected in a previous study (13). Therefore, it remains an intriguing question whether the PHD-Bromo cassettes of Sp100C and Sp140 are indeed histone readers or not.…”

mentioning

confidence: 98%

“…3B), it may contribute to such recognition by ensuring the proper folding of a functional PHD finger. This may explain why histone H3 binding activity was not observed for the Sp140 PHD finger alone on NMR-based titration studies (13). Conservation analysis (Fig.…”

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confidence: 99%

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Multifaceted Histone H3 Methylation and Phosphorylation Readout by the Plant Homeodomain Finger of Human Nuclear Antigen Sp100C

Zhang

Zhao

Xiong

et al. 2016

Journal of Biological Chemistry

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The decoding of histone post-translational modifications by chromatin-binding modules ("readers") constitutes one major mechanism of epigenetic regulation. Nuclear antigen Sp100 (SPECKLED, 100 kDa), a constitutive component of the promyelocytic leukemia nuclear bodies, plays key roles in intrinsic immunity and transcriptional repression. Sp100C, a splicing isoform specifically up-regulated upon interferon stimulation, harbors a unique tandem plant homeodomain (PHD) finger and bromodomain at its C terminus. Combining structural, quantitative binding, and cellular co-localization studies, we characterized Sp100C PHD finger as an unmethylated histone H3 Lys 4 (H3K4me0) reader that tolerates histone H3 Thr 3 phosphorylation (H3T3ph), histone H3 Lys 9 trimethylation (H3K9me3), and histone H3 Ser 10 phosphorylation (H3S10ph), hallmarks associated with the mitotic chromosome. In contrast, whereas H3K4me0 reader activity is conserved in Sp140, an Sp100C paralog, the multivalent tolerance of H3T3ph, H3K9me3, and H3S10ph was lost for Sp140. The complex structure determined at 2.1 Å revealed a highly coordinated lysine ⑀-amine recognition sphere formed by an extended N-terminal motif for H3K4me0 readout. Interestingly, reader pocket rigidification by disulfide bond formation enhanced H3K4me0 binding by Sp100C. An additional complex structure solved at 2.7 Å revealed that H3T3ph is recognized by the arginine residue, Arg 713 , that is unique to the PHD finger of Sp100C. Consistent with a restrictive cellular role of Sp100C, these results establish a direct chromatin targeting function of Sp100C that may regulate transcriptional gene silencing and promyelocytic leukemia nuclear body-mediated intrinsic immunity in response to interferon stimulation.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Multifaceted Histone H3 Methylation and Phosphorylation Readout by the Plant Homeodomain Finger of Human Nuclear Antigen Sp100C

Zhang

Zhao

Xiong

et al. 2016

Journal of Biological Chemistry

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“…The two isoforms of SP140 themselves were most highly correlated (average correlation 0.91; turquoise module; Supplemental Table 3), followed by the gene pair SP140 and IKZF3 (average correlation 0.88; Figure 5 and Supplemental Figure 10). SP140 contains a bromodomain and a plant homeodomain that recognize and bind acetylated and methylated histones, respectively, and are found in multiple epigenetic “readers” (21). SP140 is hypothesized to act in immune tolerance or acute viral immunity (22).…”

Section: Resultsmentioning

confidence: 99%

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

Peloquin¹,

Goel²,

Kong³

et al. 2016

JCI Insight

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GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn’s disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis.

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Specificity Analysis of Histone Modification-Specific Antibodies or Reading Domains on Histone Peptide Arrays

Kungulovski

Kycia

Mauser

et al. 2015

Methods in Molecular Biology

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Histone posttranslational modifications (PTMs) have a crucial role in chromatin regulation and dynamics. They are specifically bound by so-called reading domains, which mediate the biological effects of histone PTMs. On a similar note, antibodies are invaluable reagents in chromatin biology for the detection, characterization, and mapping of histone PTMs. Despite these central roles in chromatin research and biology, the specificity of many antibodies and reading domains has been insufficiently characterized and documented. Here we describe in detail the application of the MODified™ Histone Peptide Array for the investigation of the binding specificity of histone binding antibodies or domains. The array contains 384 histone tail peptides carrying 59 posttranslational modifications in different combinations which can be used to study the primary binding specificity, but at the same time also allow to determine the combinatorial effect of secondary marks on antibody or reading domain binding.

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Structure of human Sp140 PHD finger: an atypical fold interacting with Pin1

Cited by 17 publications

References 64 publications

Multifaceted Histone H3 Methylation and Phosphorylation Readout by the Plant Homeodomain Finger of Human Nuclear Antigen Sp100C

Multifaceted Histone H3 Methylation and Phosphorylation Readout by the Plant Homeodomain Finger of Human Nuclear Antigen Sp100C

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

Specificity Analysis of Histone Modification-Specific Antibodies or Reading Domains on Histone Peptide Arrays

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