RT Journal Article
SR Electronic
T1 Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 620260
DO 10.1101/620260
A1 Stephen Watt
A1 Louella Vasquez
A1 Klaudia Walter
A1 Alice L. Mann
A1 Kousik Kundu
A1 Lu Chen
A1 Ying Yan
A1 Simone Ecker
A1 Frances Burden
A1 Samantha Farrow
A1 Ben Farr
A1 Valentina Iotchkova
A1 Heather Elding
A1 Daniel Mead
A1 Manuel Tardaguila
A1 Hannes Ponstingl
A1 David Richardson
A1 Avik Datta
A1 Paul Flicek
A1 Laura Clarke
A1 Kate Downes
A1 Tomi Pastinen
A1 Peter Fraser
A1 Mattia Frontini
A1 Biola-Maria Javierre
A1 Mikhail Spivakov
A1 Nicole Soranzo
YR 2019
UL http://biorxiv.org/content/early/2019/04/29/620260.abstract
AB Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.