The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation

Abstract

Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and regulate other immune cells by cytokine secretion. Whereas murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells (hESC) and by expressing the dominant-negative ETS1 p27 isoform in cord blood (CB) hematopoietic progenitor cells (HPCs), we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation, i.e. E4BP4, TXNIP, TBET, GATA3, HOBIT and BLIMP1. In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation.

Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

“…NFKB, IRF7, PAX5). In particular, ETS1 has been previously demonstrated to direct NK cell differentiation [36]. We observed no significant enrichment between secondary conditional eQTL in NK cells and transcription factor binding sites.…”

Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development

“…The founding member of the ETS transcription family ETS-1 shows extensive sequence conservation among vertebrates and alongside its sibling ETS-2 has critical roles in the development of the heart and circulatory system [ 25 , 26 , 27 ]. In adult humans, mice and chickens, ETS-1 expression is particularly localized to immune tissues (e.g., thymus, spleen and lymph nodes in mice), consistent with roles in regulating B cell, T cell and NK cell differentiation, whereas ETS-2 expression is more widespread [ 11 , 25 , 28 ].…”

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

“…Despite the negative regulation of T-bet expression by FoxO1, several transcription factors, including GATA binding protein 3 (GATA3), thymocyte selection-associated HMG box 2 (TOX2) and Ets proto-oncogene 1 (ETS-1), promote T-bet expression (138)(139)(140)(141). Thus, inactivation of FoxO1 mediated by IL-15 − PI3K − mTORC2 signaling coordinated with several transcription factors to promote T-bet expression.…”