Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality

Abstract

Summary Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cells counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naïve CD4+ T cells during Th cell differentiation using a type 2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

“…If so, then another way to see Bcl11b's role at the DN2b stage is that it imposes a temporal delay between the time that these genes could be initially specified for activity (in DN2b pro-T cells) and the time that mature TCR-αβ T cells (their much later descendants) will be allowed to deploy them. As we and others have discussed previously (60,61), the timing of deployment of the effector response gene subnetwork distinguishes αβ-TCR + T cells, γδ-TCR + T cells, and ILCs more profoundly than the actual effector response networks themselves. Some of the targets we see up-regulated in Bcl11b KOs in fact include genes specific for certain γδ lineages (e.g., Cd163l1, Tnni1, and certain Tcrg transcripts).…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Recent high‐resolution epigenetic and transcriptomic analyses of human and murine ILC3 have begun to clarify subset‐specific functional and transcriptional phenotypes, while revealing that ILC3 exhibit a higher degree of plasticity and heterogeneity than previously appreciated 56, 57, 58, 59, 60. Despite sharing many overlapping transcriptional pathways LTi‐like and NKp46 + ILC3 subsets exhibit considerable differences in chromatin accessibility and predicted transcription factor occupancy among accessible gene regulatory elements 58, 59, 60. Differences between these two canonical ILC3 subsets are further highlighted on the transcriptional level 56, 60.…”

The Interplay between Transcription Factors and Epigenetic Modifications in Th2 Cells

“…A study of human Th2 cells indicated that STAT6 binding was hardly detected at the GATA3 gene locus, although STAT6 knockdown was efective for reducing the GATA3 expression [18]. Interestingly, our ChIP-seq analysis detected one GATA3 binding peak close to one of the STAT6 binding sites at the Gata3 gene locus [8,51] and one of the strong peaks on the assay for transposase-accessible chromatin sequencing (ATAC-seq) [63]. This GATA3 binding site may be important for cis-regulation via GATA3-dependent auto activation of the Gata3 gene [36].…”

“…Indeed, GATA3 associates with RNA polymerase II and CBP/p300, which contain histone acetyltransferase activity at this region [73]. In addition, CGRE is located at the 5′ edge of the accessible DNA region detected by ATAC-seq [63]. Thus, the CGRE region may play an important role in Il13 transcription and in chromatin remodeling at the Il13 locus.…”

“…This region also contains binding sites for STAT5, which has been reported to be important for the maintenance of DNA accessibility of this region in Th2 cells [23,83]. Correspondingly, a strong ATAC-seq peak was detected at this region in Th2 cells [63]. Recently, a group reported that genetic deletion of HSII resulted in a reduction in IL-4 but not IL-13 production, implying its role in regulating IL-4 production [74].…”