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Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells

67 Pages Posted: 27 Nov 2018 Sneak Peek Status: Published

See all articles by Maria Pokrovskii

Maria Pokrovskii

New York University (NYU) - The Kimmel Center for Biology and Medicine

Jason A. Hall

New York University (NYU) - The Kimmel Center for Biology and Medicine

David E. Ochayon

University of Cincinnati - Department of Pediatrics

Ren Yi

New York University (NYU) - Department of Biology

Natalia S. Chaimowitz

University of Cincinnati - Department of Pediatrics

Harsha Seelamneni

University of Cincinnati - Department of Pediatrics

Nicholas Carriero

Flatiron Institute - Center for Computational Biology

Aaron Watters

Flatiron Institute - Center for Computational Biology

Stephen N. Waggoner

University of Cincinnati - Department of Pediatrics

Dan R. Littman

New York University (NYU) - The Kimmel Center for Biology and Medicine

Richard Bonneau

New York University (NYU) - Center for Genomics and Systems Biology

Emily R. Miraldi

University of Cincinnati - Department of Pediatrics

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Abstract

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.

Keywords: Gene regulation; ATAC-seq; lineage commitment; inferelator; lymphocyte development

Suggested Citation

Pokrovskii, Maria and Hall, Jason A. and Ochayon, David E. and Yi, Ren and Chaimowitz, Natalia S. and Seelamneni, Harsha and Carriero, Nicholas and Watters, Aaron and Waggoner, Stephen N. and Littman, Dan R. and Bonneau, Richard and Miraldi, Emily R., Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells (November 27, 2018). Available at SSRN: https://ssrn.com/abstract=3291328 or http://dx.doi.org/10.2139/ssrn.3291328
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Maria Pokrovskii

New York University (NYU) - The Kimmel Center for Biology and Medicine

540 First Avenue
New York, NY 10016
United States

Jason A. Hall

New York University (NYU) - The Kimmel Center for Biology and Medicine

540 First Avenue
New York, NY 10016
United States

David E. Ochayon

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Ren Yi

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Natalia S. Chaimowitz

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Harsha Seelamneni

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Nicholas Carriero

Flatiron Institute - Center for Computational Biology

New York, NY 10010
United States

Aaron Watters

Flatiron Institute - Center for Computational Biology

New York, NY 10010
United States

Stephen N. Waggoner

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Dan R. Littman (Contact Author)

New York University (NYU) - The Kimmel Center for Biology and Medicine ( email )

540 First Avenue
New York, NY 10016
United States

Richard Bonneau

New York University (NYU) - Center for Genomics and Systems Biology ( email )

New York, NY
United States

Emily R. Miraldi

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

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