scholarly journals Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

2018 ◽  
Author(s):  
Maria Pokrovskii ◽  
Jason A. Hall ◽  
David E. Ochayon ◽  
Ren Yi ◽  
Natalia S. Chaimowitz ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Inflammatory Diseases ◽  
Innate Lymphoid Cells ◽  
Chromatin Accessibility ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory

SummaryInnate 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 otherin vivocell populations.

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

Immunity ◽  
2019 ◽  
Vol 51 (1) ◽  
pp. 185-197.e6 ◽  
Author(s):  
Maria Pokrovskii ◽  
Jason A. Hall ◽  
David E. Ochayon ◽  
Ren Yi ◽  
Natalia S. Chaimowitz ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory

scholarly journals Vegfaexpression is activated through positive and negative transcriptional regulatory networks controlled by the ETS factor Etv6in vivo

2018 ◽  
Author(s):  
Lei Li ◽  
Rossella Rispoli ◽  
Roger Patient ◽  
Aldo Ciau-Uitz ◽  
Catherine Porcher
Keyword(s):  
Regulatory Networks ◽  
Dual Function ◽  
Transcriptional Regulatory Networks ◽  
Pathological Angiogenesis ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
Ets Transcription Factor ◽  
Endothelial Development ◽  
New Strategies

AbstractVEGFA signaling is crucial for physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered, vegfa transcriptional regulation in vivo remains unclear. Here we show that the ETS transcription factor, Etv6, positively regulates vegfa expression during Xenopus blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits the expression of the vegfa repressor, foxo3. Surprisingly, it also directly activates the expression of the vegfa activator, klf4. Finally, it indirectly binds to the vegfa promoter where it co-localizes with Klf4. Klf4 deficiency downregulates vegfa expression and significantly decreases Etv6 binding to the vegfa promoter, indicating that Klf4 recruits Etv6 to the vegfa promoter. Thus, our work uncovers a dual function for Etv6, as both a transcriptional repressor and activator, in controlling a major signaling pathway involved in blood and endothelial development in vivo. Given the established relationships between development and cancer, this elaborate gene regulatory network may inform new strategies for the treatment of VEGFA-dependent tumorigenesis.

scholarly journals Non-adaptive factors determine which equally effective regulatory motif evolves to generate pulses

2020 ◽  
Author(s):  
Kun Xiong ◽  
Mark Gerstein ◽  
Joanna Masel
Keyword(s):  
Regulatory Networks ◽  
De Novo ◽  
Superior Performance ◽  
Network Motifs ◽  
Transcriptional Regulatory Networks ◽  
Expression Levels ◽  
Negative Feedback Loops ◽  
Transcriptional Regulatory ◽  
Relative Functionality

AbstractTranscriptional regulatory networks (TRNs) are enriched for certain subnetworks or “motifs”. Motif usage is commonly interpreted as the result of adaptive evolution. But network motifs can also differ in how easy it is to evolve them. Here, we simulated the de novo evolution of motifs within TRNs under selection to produce a short, sharp pulse of an effector protein. In agreement with past work in the field, two network motifs, type 1 incoherent feed-forward loops (I1FFLs) and negative feedback loops (NFBLs), evolved as the primary solutions. Different selection conditions changed the relative frequencies of the two solutions, but this was not due to the superior performance of one; under all conditions, either motif can achieve similar top performance. I1FFLs generally evolve more often than NFBLs, unless we selected for a particularly tall pulse. This result suggests that I1FFLs are evolutionary more accessible than NFBLs. When NFBLs do evolve, it is usually from a conjugate containing both I1FFL and NFBL. In contrast, I1FFLs can evolve via a greater variety of trajectories. This difference potentially explains NFBL’s lower evolutionary accessibility. To agreement with our simulation results, we found that in the real yeast TRN, output genes of NFBLs had higher expression levels than those of I1FFLs, i.e. selection for taller pulses. These results suggest that evolutionary accessibility, and not relative functionality, shape which networks motifs evolve in TRNs, and do so as a function of the expression levels of particular genes.

Differences in evolutionary accessibility determine which equally effective regulatory motif evolves to generate pulses

Genetics ◽  
2021 ◽  
Author(s):  
Kun Xiong ◽  
Mark Gerstein ◽  
Joanna Masel
Keyword(s):  
Regulatory Networks ◽  
Fast Response ◽  
Effector Protein ◽  
Transcriptional Regulatory Networks ◽  
Expression Levels ◽  
Negative Feedback Loops ◽  
Transcriptional Regulatory ◽  
Selection For ◽  
Relative Functionality

Abstract Transcriptional regulatory networks (TRNs) are enriched for certain “motifs”. Motif usage is commonly interpreted in adaptationist terms, i.e. that the optimal motif evolves. But certain motifs can also evolve more easily than others. Here, we computationally evolved TRNs to produce a pulse of an effector protein. Two well-known motifs, type 1 incoherent feed-forward loops (I1FFLs) and negative feedback loops (NFBLs), evolved as the primary solutions. The relative rates at which these two motifs evolve depend on selection conditions, but under all conditions, either motif achieves similar performance. I1FFLs generally evolve more often than NFBLs. Selection for a tall pulse favors NFBLs, while selection for a fast response favors I1FFLs. I1FFLs are more evolutionarily accessible early on, before the effector protein evolves high expression; when NFBLs subsequently evolve, they tend to do so from a conjugated I1FFL-NFBL genotype. In the empirical S. cerevisiae TRN, output genes of NFBLs had higher expression levels than those of I1FFLs. These results suggest that evolutionary accessibility, and not relative functionality, shapes which motifs evolve in TRNs, and does so as a function of the expression levels of particular genes.

scholarly journals Innate lymphoid cells in the upper airways: importance of CD117 and IL-1RI expression

2018 ◽  
Vol 52 (6) ◽  
pp. 1800742 ◽  
Author(s):  
Koen Van Crombruggen ◽  
Sylvie Taveirne ◽  
Gabriele Holtappels ◽  
Georges Leclercq ◽  
Claus Bachert
Keyword(s):  
Nasal Polyps ◽  
Upper Airway ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Type I ◽  
Upper Airways ◽  
Airway Mucosa

Although type 1, 2 and 3 innate lymphoid cells (ILC1s, ILC2s and ILC3s, respectively) are emerging as important cell populations regulating tissue homeostasis, remodelling and inflammation, a vast majority of our knowledge stems from in vitro and murine experiments, and requires thorough confirmation in human diseases.Relative levels of ILCs were evaluated by means of flow cytometry in freshly resected human upper airways mucosa of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP), taking into account the patient's clinical parameters and disease comorbidities.We report that the CD117 and interleukin-receptor type I (IL-1RI) expression status of human ILC2s depends on the local tissue environment. Only CD117+ IL-1RI+ ILC2s, exclusively present in CRSwNP, possess an interrelationship with type 2 T-helper cell cytokine and eosinophil levels in human upper airway mucosa. In CRSsNP, mainly CD117−IL-1RI− ILC2s are increased, yielding lower eosinophilia in this disease despite the high levels of ILC2s.These data unveil that the CD117− and CD117+ fractions within the native human ILC2 population are not a random phenomenon, in contrast to what could be concluded from in vitro data, and that the IL-1RI expression is not ubiquitous in ILC2s in vivo in humans, which cannot be assessed via in vitro and murine experiments.

scholarly journals Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mingsen Li ◽  
Huaxing Huang ◽  
Lingyu Li ◽  
Chenxi He ◽  
Liqiong Zhu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Regulatory Networks ◽  
Adult Stem Cell ◽  
Chromatin Accessibility ◽  
Transcriptional Regulatory Networks ◽  
Cell Identity ◽  
Corneal Epithelial ◽  
Epithelial Homeostasis ◽  
Super Enhancer ◽  
Transcriptional Regulatory

AbstractAdult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis.

scholarly journals Sustained post-developmental T-bet expression is critical for the maintenance of type 1 innate lymphoid cells in vivo

2021 ◽  
Author(s):  
Jan-Hendrik Schroeder ◽  
Luke B Roberts ◽  
Katrin Meissl ◽  
Jon W Lo ◽  
Dominika Hromadova ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Immune Response ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Inflammatory Bowel Disease ◽  
Inflammatory Bowel ◽  
Subsequent Loss ◽  
Th1 Polarization

Innate lymphoid cells (ILC) play a significant role in the intestinal immune response and T-bet+ CD127+ group 1 cells (ILC1) have been linked to the pathogenesis of human inflammatory bowel disease (IBD). However, the functional importance of ILC1 in the context of an intact adaptive immune response has been controversial. In this report we demonstrate that induced depletion of T-bet using a Rosa26-Cre-ERT2 model resulted in the loss of intestinal ILC1, pointing to a post-developmental requirement of T-bet expression for these cells. Surprisingly, neither colonic intraepithelial ILC1, colonic lamina propria (cLP) ILC2 nor cLP ILC3 abundance were altered upon induced deletion of T-bet. Furthermore, Th1 polarization was not significantly altered upon induced T-bet deletion in vivo. Mechanistically, we report that STAT1 or STAT4 are not required for intestinal ILC1 development and maintenance. Mice with induced deletion of T-bet and subsequent loss of ILC1 were protected from the induction of severe colitis in vivo. Hence, this study provides support for the clinical development of an IBD treatment based on ILC1 depletion via targeting T-bet or its downstream transcriptional targets.

scholarly journals c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Morgan E. Parker ◽  
Alejandro Barrera ◽  
Joshua D. Wheaton ◽  
Matthew K. Zuberbuehler ◽  
David S.J. Allan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Chromatin Accessibility ◽  
Lymphoid Cells ◽  
Global Changes ◽  
Intestinal Immunity ◽  
Phenotypic Analysis ◽  
Group 3 ◽  
And Function

CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

scholarly journals CD5 Surface Expression Marks Intravascular Human Innate Lymphoid Cells That Have a Distinct Ontogeny and Migrate to the Lung

2021 ◽  
Vol 12 ◽  
Author(s):  
Arlisa Alisjahbana ◽  
Yu Gao ◽  
Natalie Sleiers ◽  
Elza Evren ◽  
Demi Brownlie ◽  
...  
Keyword(s):  
Surface Expression ◽  
Innate Lymphoid Cells ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Effector Cytokines

Innate lymphoid cells (ILCs) contribute to immune defense, yet it is poorly understood how ILCs develop and are strategically positioned in the lung. This applies especially to human ILCs due to the difficulty of studying them in vivo. Here we investigated the ontogeny and migration of human ILCs in vivo with a humanized mouse model (“MISTRG”) expressing human cytokines. In addition to known tissue-resident ILC subsets, we discovered CD5-expressing ILCs that predominantly resided within the lung vasculature and in the circulation. CD5+ ILCs contained IFNγ-producing mature ILC1s as well as immature ILCs that produced ILC effector cytokines under polarizing conditions in vitro. CD5+ ILCs had a distinct ontogeny compared to conventional CD5- ILCs because they first appeared in the thymus, spleen and liver rather than in the bone marrow after transplantation of MISTRG mice with human CD34+ hematopoietic stem and progenitor cells. Due to their strategic location, human CD5+ ILCs could serve as blood-borne sentinels, ready to be recruited into the lung to respond to environmental challenges. This work emphasizes the uniqueness of human CD5+ ILCs in terms of their anatomical localization and developmental origin compared to well-studied CD5- ILCs.

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