A Multiomics Resource of B Cell Activation Helps Decipher Disease Pathogenesis

Nada Abdel-Aziz – Boston Children’s Hospital, Harvard Medical School; Emily Banasiak – Brigham and Women's Hospital, Harvard Medical School; Mehdi Benamar – Boston Children’s Hospital, Harvard Medical School; Junning Case – Brigham and Women’s Hospital, Harvard Medical School; Kevin Cashman – Emory University; Paloma Cejas – Dana-Farber Cancer Institute, Harvard Medical School; Margaret Chang – Boston Children’s Hospital, Harvard Medical School; Marcos Chinas – Boston Children’s Hospital, Harvard Medical School; Mariasilvia Colantuoni – Boston Children’s Hospital, Harvard Medical School; Roxane Darbousset – Boston Children’s Hospital, Harvard Medical School; Daniela Fernandez-Salinas – Boston Children’s Hospital, Harvard Medical School; Marcella Franco – Boston Children's Hospital, Harvard Medical School; Miguel Gomez – Dana-Farber Cancer Institute, Harvard Medical School; Maria Gutierrez-Arcelus – Boston Children’s Hospital, Harvard Medical School; Nicolaj Hackert – Heidelberg University Hospital; Lauren Henderson – Boston Children’s Hospital, Harvard Medical School; Scott Jenks – Emory University; Carl Langefeld – Wake Forest School of Medicine; Raquel Laza-Briviesca – Boston Children’s Hospital, Harvard Medical School; Pui Lee – Boston Children’s Hospital, Harvard Medical School; Henry Long – Dana-Farber Cancer Institute, Harvard Medical School; Esra Meidan – Boston Children’s Hospital, Harvard Medical School; Peter Nigrovic – Boston Children’s Hospital, Harvard Medical School; Vaishali Prahalad – Emory University; Ignacio Sanz – Emory University; Jeffrey Sparks – Brigham and Women’s Hospital, Harvard Medical School; Marc Todd – Virginia Tech University; Alex Wactor – Boston Children’s Hospital, Harvard Medical School; Qiang Wang – Boston Children’s Hospital, Harvard Medical School; Brian Wauford – Boston Children’s Hospital, Hospital; Kevin Wei – Brigham and Women’s Hospital, Harvard Medical School; Qian Xiao – Boston Children’s Hospital, Harvard Medical School; Zhu Zhu – Brigham and Women's Hospital, Harvard Medical School; Esther Zumaquero – University of Alabama at Birmingham

Abstract Text: Most genetic variants that confer risk of complex immune-mediated diseases (IMD) affect gene regulation in specific cell types. Their target genes and focus cell types are often unknown, partially because some effects are hidden in untested cell states. B cells are drivers of IMDs such as lupus and multiple sclerosis. Yet, B cell activation states are underrepresented in functional genomics studies. In this study, we obtained B cells from a total of 26 healthy female donors. We stimulated B cells in vitro by targeting key pathways in six activation conditions such as the CD40, BCR, TLR7, TLR9, and a cocktail that promotes differentiation into double negative 2 (DN2) IgD- CD27- CD11c+ B cells. We profiled B cell activation at different time points using RNA-seq, single-cell RNA-seq coupled with surface protein markers (CITE-seq), and ATAC-seq. We provide an in-depth characterization of how IMD-associated genes respond to stimuli and group into modules with distinct functions. Using single-cell data, we describe pathway-dependent B cell fates. Chromatin data reveal the transcription factors involved in pathway-dependent B cell activation. These open chromatin regions capture a significant proportion of the genetic risk of IMDs and elucidate IMD genetic risk variants with previously unknown function. These data are shared via an interactive browser that can be used to query the dynamics of gene regulation and B cell differentiation during activation by different stimuli.