RT Journal Article
SR Electronic
T1 Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 465435
DO 10.1101/465435
A1 Maria Pokrovskii
A1 Jason A. Hall
A1 David E. Ochayon
A1 Ren Yi
A1 Natalia S. Chaimowitz
A1 Harsha Seelamneni
A1 Nicholas Carriero
A1 Aaron Watters
A1 Stephen N. Waggoner
A1 Dan R. Littman
A1 Richard Bonneau
A1 Emily R. Miraldi
YR 2018
UL http://biorxiv.org/content/early/2018/11/08/465435.abstract
AB Innate lymphoid cells (ILCs) can be subdivided into several distinct cytokine-secreting lineages that promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Accumulating evidence suggests that ILCs, similarly to other immune populations, are capable of phenotypic and functional plasticity in response to infectious or environmental stimuli. Yet the transcriptional circuits that control ILC identity and function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer transcriptional regulatory networks within intestinal type 1, 2, and 3 ILCs. We predict the “core” sets of transcription-factor (TF) regulators driving each ILC subset identity, among which only a few TFs were previously known. To assist in the interpretation of these networks, TFs were organized into cooperative clusters, or modules that control gene programs with distinct functions. The ILC network reveals extensive alternative-lineage-gene repression, whose regulation may explain reported plasticity between ILC subsets. We validate new roles for c-MAF and BCL6 as regulators affecting the type 1 and type 3 ILC lineages. Manipulation of TF pathways identified here might provide a novel means to selectively regulate ILC effector functions to alleviate inflammatory disease or enhance host tolerance to pathogenic microbes or noxious stimuli. Our results will enable further exploration of ILC biology, while our network approach will be broadly applicable to identifying key cell state regulators in other in vivo cell populations.