Medicine and Health Sciences Commons^™

Rheumatoid Arthritis-Relevant Dna Methylation Changes Identified In Acpa-Positive Asymptomatic Individuals Using Methylome Capture Sequencing., Xiaojian Shao, Marie Hudson, Ines Colmegna, Celia M T Greenwood, Marvin J. Fritzler, Philip Awadalla, T Pastinen, Sasha Bernatsky

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.

METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. …

Ucp1 Expression-Associated Gene Signatures Of Human Epicardial Adipose Tissue., Kanta Chechi, Jinchu Vijay, Pierre Voisine, Patrick Mathieu, Yohan Bossé, Andre Tchernof, Elin Grundberg, Denis Richard

Manuscripts, Articles, Book Chapters and Other Papers

Multiple reports of uncoupling protein 1 (UCP1) expression have established its presence in human epicardial adipose tissue (eAT). Its functional relevance to eAT, however, remains largely unknown. In a recent study, we reported that adrenergic stimulation of eAT was associated with downregulation of secreted proteins involved in oxidative stress-related and immune-related pathways. Here, we explored the UCP1-associated features of human eAT using next-generation deep sequencing. Paired biopsies of eAT, mediastinal adipose tissue (mAT), and subcutaneous adipose tissue (sAT) obtained from cardiac surgery patients, with specific criteria of high and low expression of UCP1 in eAT, were subjected to RNA sequencing. …

H3k27m Induces Defective Chromatin Spread Of Prc2-Mediated Repressive H3k27me2/Me3 And Is Essential For Glioma Tumorigenesis., Ashot S. Harutyunyan, Brian Krug, Haifen Chen, Simon Papillon-Cavanagh, Michele Zeinieh, Nicolas De Jay, Shriya Deshmukh, Carol C L Chen, Jad Belle, Leonie G. Mikael, Dylan M. Marchione, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K. Mcconechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Jacek Majewski

Manuscripts, Articles, Book Chapters and Other Papers

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on …

Dissecting Features Of Epigenetic Variants Underlying Cardiometabolic Risk Using Full-Resolution Epigenome Profiling In Regulatory Elements., Fiona Allum, Åsa K. Hedman, Xiaojian Shao, Warren A. Cheung, Jinchu Vijay, Frédéric Guénard, Tony Kwan, Marie-Michelle Simon, Bing Ge, Cristiano Moura, Elodie Boulier, Lars Rönnblom, Sasha Bernatsky, Mark Lathrop, Mark I. Mccarthy, Panos Deloukas, André Tchernof, T Pastinen, Marie-Claude Vohl, Elin Grundberg

Manuscripts, Articles, Book Chapters and Other Papers

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up …

Effect Of Conditioning Regimen Dose Reduction In Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation., Claudio G. Brunstein, Marcelo C. Pasquini, Soyoung Kim, Mingwei Fei, Kehinde Adekola, Ibrahim A. Ahmed, Mahmoud Aljurf, Vaibhav Agrawal, Jeffrey J. Auletta, Minoo Battiwalla, Nelli Bejanyan, Joseph Bubalo, Jan Cerny, Lynette Chee, Stefan O. Ciurea, Cesar Freytes, Shahinaz M. Gadalla, Robert Peter Gale, Siddhartha Ganguly, Shahrukh K. Hashmi, Peiman Hematti, Gerhard Hildebrandt, Leona A. Holmberg, Oscar B. Lahoud, Heather Landau, Hillard M. Lazarus, Marcos De Lima, Vikram Mathews, Richard Maziarz, Taiga Nishihori, Maxim Norkin, Richard Olsson, Ran Reshef, Seth Rotz, Bipin Savani, Harry C. Schouten, Sachiko Seo, Baldeep M. Wirk, Jean Yared, Shin Mineishi, John Rogosheske, Miguel-Angel Perales

Manuscripts, Articles, Book Chapters and Other Papers

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

Manuscripts, Articles, Book Chapters and Other Papers

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …