Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

Abstract

Summary Commitment to the innate lymphoid cells (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Thus, non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs.

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…Like STAT3, STAT5A and STAT5B are also activated by many cytokines including important hematopoietic factors like erythropoietin (EPO) and CSFs. In lymphocytes, STAT5 drives differentiation of innate lymphoid cells, promotes regulatory cell phenotype (Treg) and Foxp3 expression, and inhibits Th17 and follicular helper T cell differentiation …”

“…In lymphocytes, STAT5 drives differentiation of innate lymphoid cells, promotes regulatory cell phenotype (Treg) and Foxp3 expression, and inhibits Th17 and follicular helper T cell differentiation. 10,11…”

JAK/STAT signaling in regulation of innate lymphoid cells: The gods before the guardians

“…However, it is highly probable that thanks to the rapid advances of “single cell” technology this knowledge gap will be soon filled. In comparison to other STATs, the mechanisms of gene regulation by STAT5 have been more extensively studied and better delineated . Beyond the identification of genes undergoing positive and negative regulation, the analysis of genomic distribution of STAT5 has revealed a widespread DNA binding both in unstimulated and IL‐15‐stimulated NK cells .…”

“…Regulation of Id2 gene by STAT5 occurs in mice with a peculiar mechanism involving a cis‐DRE associated with a long noncoding RNA (lncRNA), named Rroid (RNA‐demarcated regulatory region of ID2) . While Rroid is specifically expressed in type 1 ILCs, only the Rroid locus, but not the lncRNA itself, is required for the adequate STAT5 occupancy of the Id2 promoter and transcription of this gene in ILC1.…”

Transcriptional control of natural killer cell differentiation

“…For example, the histone H2A deubiquitinase MYSM1 promotes NK cell development by maintaining an open chromatin configuration at the Id2 locus and by facilitating the recruitment of Nfil3 to the Id2 promoter . More recently, it was shown that a cis ‐regulatory element in the long non‐coding RNA (lncRNA), RNA demarcated regulatory region of Id2 ( Rroid ), that is located upstream of Id2 critically regulates NK cell identity and homeostasis . Acting through long‐range interactions, Rroid promotes chromatin accessibility and STAT5 recruitment to the Id2 locus, thereby enhancing ID2 expression.…”