Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation

Michieletto, M.; Tello-Cajiao, John J.; Mowel, Walter K.; Chandra, Aditi; Yoon, Sora; Joannas, Leonel; Clark, Megan L.; Jimenez, Monica T.; Wright, Jasmine M.; Lundgren, Patrick; Williams, Adam; Thaiss, Christoph A.; Vahedi, Golnaz; Henao‐Mejia, Jorge

doi:10.1038/s41590-022-01295-y

Cited by 13 publications

(8 citation statements)

References 69 publications

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“…Within the larger hierarchical structures, we found that innate and adaptive lymphocytes share high proportions of compartments and TADs that are largely stable throughout effector and memory differentiation. In support of our findings, previous studies in lymphocyte development suggest that higher-order structures are established as early as the common lymphoid progenitor (CLP) stage, with relatively little changes occurring after the CLP and during acute inflammatory response, consistent with the idea that the higher-order structures may be acting as a scaffold to facilitate cell type-specific functions 7,20,31,32 . However, how these larger structures are established during lymphocyte development and antiviral responses, and what factors shape the higher-order structures within innate and adaptive lymphocytes, warrant further investigation.…”

Section: Discussionsupporting

confidence: 91%

3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

Santosa

Lau

Şahin³

et al. 2023

Preprint

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Immune cells responding to pathogens undergo molecular changes that are intimately linked to genome organization. Recent work has demonstrated that natural killer (NK) and CD8+ T cells experience substantial transcriptomic and epigenetic rewiring during their differentiation from naive to effector to memory cells. Whether these molecular adaptations are accompanied by changes in three-dimensional (3D) chromatin architecture is unknown. In this study, we combine histone profiling, ATAC-seq, RNA-seq and high-throughput chromatin capture (HiC) assay to investigate the dynamics of one-dimensional (1D) and 3D chromatin during the differentiation of innate and adaptive lymphocytes. To this end, we discovered a coordinated 1D and 3D epigenetic remodeling during innate immune memory differentiation, and demonstrate that effector CD8+ T cells adopt an NK-like architectural program that is maintained in memory cells. Altogether, our study reveals the dynamic nature of the 1D and 3D genome during the formation of innate and adaptive immunological memory.

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Section: Discussionsupporting

confidence: 91%

3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

Santosa

Lau

Şahin³

et al. 2023

Preprint

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“…ILC3s are a relatively rare cell type that cannot be easily expanded in vivo , which makes their chromosomal interaction profiling challenging. Indeed, this problem has precluded ILC3 profiling by standard Hi-C alongside their Type 2 ILC counterparts in a very recent mouse study 96 . Robust Capture Hi-C profiling typically requires even higher cell numbers.…”

Section: Discussionmentioning

confidence: 99%

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Malysheva

Ray-Jones

Cazares

et al. 2022

Preprint

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Innate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries underlying ILC3 function, we used high-resolution Capture Hi-C to profile promoter-anchored chromosomal contacts in human primary ILC3s. Combining significant interaction detection with the Activity-By-Contact approach adapted to Capture Hi-C, we reveal a multitude of contacts between promoters and distal regulatory elements and obtain evidence for distinct regulatory wiring of alternative promoters. We find that promoter-interacting regions in ILC3s are enriched for genetic variants associated with multiple immune diseases. Focusing on Crohn’s disease (CD), in which ILC3s are established mediators, we used a Bayesian approach that incorporates multivariate fine-mapping to link CD-associated genetic variants with putative target genes. We identify known and previously unimplicated genes in conferring genetic risk of CD through activity in ILC3s. This includes the CLN3gene that is mutated in the neurodegenerative disorder Batten disease. UsingCln3mutant mice, we show thatCLN3is a putative negative regulator of IL-17 production in an inflammatory subset of ILC3s. This finding suggests a functional role forCLN3in ILC3 biology, with mechanistic implications for both Crohn’s and Batten diseases.

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“…Fate mapping approaches have identified successive waves of ILC2 tissue accumulation during mouse development, with the majority appearing in a postnatal wave of expansion that coincides with the upregulation of type 2 cytokine expression ( 17 ). ILC2s from fetal liver or adult bone marrow derive from common lymphoid precursors that, at default, have a genomic organization that favors ILC development and subsequently undergoes rearrangement, tethering, and looping of Id2, GATA-3, and RORα elements to become restricted to an ILC2 progenitor pool ( 18 ). Although genomic alterations driving differentiation to other ILC subsets are less well characterized, ILC1/NK and ILC3 development appear to follow similar organizing principles, as shown in fate mapping experiments tracing the development of liver-resident NK cells from ILC2 progenitors and in distinct ILC3 subsets (NCR + and NCR − ) successively arising in the mouse fetal gut, as recently overviewed ( 19 ).…”

Section: Classification and Developmental Originsmentioning

confidence: 99%

Both Horatio and Polonius: Innate Lymphoid Cells in Tissue Homeostasis and Repair

Lee,

Van Dyken

2023

ImmunoHorizons

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Innate lymphoid cells (ILCs) have emerged as critical tissue-resident lymphocytes that coordinate responses to environmental stress and injury. Traditionally, their function was thought to mirror adaptive lymphocytes that respond to specific pathogens. However, recent work has uncovered a more central role for ILCs in maintaining homeostasis even in the absence of infection. ILCs are now better conceptualized as an environmental rheostat that helps maintain the local tissue setpoint during environmental challenge by integrating sensory stimuli to direct homeostatic barrier and repair programs. In this article, we trace the developmental origins of ILCs, relate how ILCs sense danger signals, and describe their subsequent engagement of appropriate repair responses using a general paradigm of ILCs functioning as central controllers in tissue circuits. We propose that these interactions form the basis for how ILC subsets maintain organ function and organismal homeostasis, with important implications for human health.

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Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation

Cited by 13 publications

References 69 publications

3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

Both Horatio and Polonius: Innate Lymphoid Cells in Tissue Homeostasis and Repair

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