LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis

To identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple “omics” data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast‐like synoviocytes (FLS).

[1]  Xuejun Zhang,et al.  Downregulated expression of LBH mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus , 2016, The Journal of dermatology.

[2]  L. Klareskog,et al.  Mechanisms involved in triggering rheumatoid arthritis , 2016, Immunological reviews.

[3]  Manolis Kellis,et al.  HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease , 2015, Nucleic Acids Res..

[4]  Pak Chung Sham,et al.  GWASdb v2: an update database for human genetic variants identified by genome-wide association studies , 2015, Nucleic Acids Res..

[5]  N. Hannett,et al.  Transcription factor trapping by RNA in gene regulatory elements , 2015, Science.

[6]  L. Dailey,et al.  High throughput technologies for the functional discovery of mammalian enhancers: new approaches for understanding transcriptional regulatory network dynamics. , 2015, Genomics.

[7]  Wei Wang,et al.  The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast‐like Synoviocytes , 2015, Arthritis & rheumatology.

[8]  Wei Wang,et al.  Integrative Omics Analysis of Rheumatoid Arthritis Identifies Non-Obvious Therapeutic Targets , 2015, PloS one.

[9]  Matthew D. Schultz,et al.  Human Body Epigenome Maps Reveal Noncanonical DNA Methylation Variation , 2015, Nature.

[10]  P. Gregersen,et al.  High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. , 2015, Annals of the rheumatic diseases.

[11]  C. Glass,et al.  The selection and function of cell type-specific enhancers , 2015, Nature Reviews Molecular Cell Biology.

[12]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[13]  Wei Wang,et al.  Computational schemes for the prediction and annotation of enhancers from epigenomic assays. , 2015, Methods.

[14]  Qicai Liu,et al.  Limb-bud and Heart (LBH) Functions as a Tumor Suppressor of Nasopharyngeal Carcinoma by Inducing G1/S Cell Cycle Arrest , 2015, Scientific Reports.

[15]  M. Daly,et al.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants , 2014, Nature.

[16]  N. Bottini,et al.  PTPN22: the archetypal non-HLA autoimmunity gene , 2014, Nature Reviews Rheumatology.

[17]  A. Dean,et al.  Enhancer function: mechanistic and genome-wide insights come together. , 2014, Molecular cell.

[18]  Chih Lee,et al.  LASAGNA-Search 2.0: integrated transcription factor binding site search and visualization in a browser , 2014, Bioinform..

[19]  R. Shiekhattar,et al.  Where long noncoding RNAs meet DNA methylation , 2014, Cell Research.

[20]  Jun S. Liu,et al.  Genetics of rheumatoid arthritis contributes to biology and drug discovery , 2013 .

[21]  C. Glass,et al.  Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription , 2013, Nature.

[22]  R. Shoemaker,et al.  An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype , 2013, Genome Medicine.

[23]  Daniel F. Freitag,et al.  Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases , 2013, PLoS genetics.

[24]  Łukasz M. Boryń,et al.  Genome-Wide Quantitative Enhancer Activity Maps Identified by STARR-seq , 2013, Science.

[25]  S. Raychaudhuri,et al.  Genetics and epigenetics of rheumatoid arthritis , 2013, Nature Reviews Rheumatology.

[26]  Liangdan Sun,et al.  One novel susceptibility locus associate with systemic lupus erythematosus in Chinese Han population , 2013, Rheumatology International.

[27]  Martin J. Aryee,et al.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis , 2013, Nature Biotechnology.

[28]  Wei Wang,et al.  DNA methylome signature in rheumatoid arthritis , 2012, Annals of the rheumatic diseases.

[29]  N. Bottini,et al.  Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors , 2013, Nature Reviews Rheumatology.

[30]  J. Pablos,et al.  Transcriptome analysis reveals specific changes in osteoarthritis synovial fibroblasts , 2011, Annals of the rheumatic diseases.

[31]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[32]  D. Balding,et al.  Epigenome-wide association studies for common human diseases , 2011, Nature Reviews Genetics.

[33]  Robert M. Plenge,et al.  Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci , 2011, PLoS genetics.

[34]  G. Kreiman,et al.  Widespread transcription at neuronal activity-regulated enhancers , 2010, Nature.

[35]  P. Robbins,et al.  Synovial fibroblasts spread rheumatoid arthritis to unaffected joints , 2009, Nature Medicine.

[36]  Yaqin Ma,et al.  BatchPrimer3: A high throughput web application for PCR and sequencing primer design , 2008, BMC Bioinformatics.

[37]  Nathaniel D. Heintzman,et al.  Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome , 2007, Nature Genetics.

[38]  G. Firestein,et al.  Acquisition, culture, and phenotyping of synovial fibroblasts. , 2007, Methods in molecular medicine.

[39]  William Stafford Noble,et al.  Quantifying similarity between motifs , 2007, Genome Biology.

[40]  T. Huizinga,et al.  Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics , 2006, Arthritis research & therapy.

[41]  A. Joyner,et al.  Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh , 2005, Development.

[42]  W. Bugbee,et al.  Quantitative biomarker analysis of synovial gene expression by real-time PCR , 2003, Arthritis research & therapy.

[43]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.