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The transcriptional control of lineage commitment to various ILC subsets is incompletely understood. Yokoyama and colleagues show that Runx3 is essential for the normal development of ILC1 and ILC3 cells but not ILC2 cells. Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the transcription factor Runx3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. Runx3 controlled the survival of ILC1 cells but not of ILC3 cells. Runx3 was required for expression of the transcription factor RORγt and its downstream target, the transcription factor AHR, in ILC3 cells. The absence of Runx3 in ILCs exacerbated infection with Citrobacter rodentium . Therefore, our data establish Runx3 as a key transcription factor in the lineage-specific differentiation of ILC1 and ILC3 cells.

The transcription factor Runx3 is identified as a central regulator of the development of tissue-resident memory CD8 + T cells, providing insights into the signals that promote T cell residency in non-lymphoid tissues and tumours. T cell residency run by Runx3 Memory T cells that reside in tissues around the body are positioned at points that are commonly exposed to pathogens, ready to launch their immune response. However, the molecular signals that control their activity here are not well understood. In this study Ananda Goldrath and co-workers identify the transcription factor Runx3 as a key regulator of the development and functionality of tissue-resident memory CD8 + T cells. They provide evidence that supports the establishment of a residence-fate commitment early during CD8 + T cell differentiation. Tissue-resident memory CD8 + T (T RM ) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses 1 , 2 . However, the molecular signals that control T RM cell differentiation and homeostasis are not fully understood. Here we show that mouse T RM precursor cells represent a unique CD8 + T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of T RM cell differentiation and homeostasis. Runx3 was required to establish T RM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with T RM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3 -deficient CD8 + tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8 + T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of T RM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice. Molecular diversity of proprioceptive neuron types (Ia, Ib and II PNs) is unclear. Here, the authors characterized the functional organization and development of eight subtypes of PNs in mice. Importantly, Ia subtypes are plastic, suggesting a role in adaptive proprioception during motor behavior.

m 6 A RNA methylation is essential for many aspects of mammalian development but its roles in chondrogenesis remain largely unknown. Here, we show that m 6 A is necessary for chondrogenesis and limb morphogenesis using limb progenitor-specific knockout mice of Mettl14 , an essential subunit in the m 6 A methyltransferase complex. The knockout disrupts cartilage anlagen formation in limb buds with 11 downregulated proteins known to dysregulate chondrogenesis and shorten limb skeletons upon mutation in mice and humans. Further studies show a gene regulatory hierarchy among the 11 proteins. m 6 A stabilizes the transcript and increases the protein level of GDF5, a BMP family member. This activates the chondrogenic transcription factor genes Runx2 and Runx3 , whose mRNAs are also stabilized by m 6 A. They promote the transcription of six collagen genes and two other chondrogenic genes, Ddrgk1 and Pbxip1 . Thus, this study uncovers an m 6 A-based cascade essential for chondrogenesis during limb skeletal development. Recent work shows that m6A RNA methylation is an important regulatory mechanism during development. Here they show that the m6A RNA methylase subunit METTL14 plays a critical role in chondrogenesis during mouse limb development, where it stabilizes Gdf5 and Runx2/3 mRNAs.

While biomarkers have been shown to enhance the prognosis of patients with colorectal cancer (CRC) compared to conventional treatments, there is a pressing need to discover novel biomarkers that can assist in assessing the prognostic impact of immunotherapy and in formulating individualized treatment plans. The RUNX family, consisting of RUNX1, RUNX2, and RUNX3, has been recognized as crucial regulators in developmental processes, with dysregulation of these genes also being implicated in tumorigenesis and cancer progression. In our present study, we demonstrated a crucial regulatory role of RUNX in CD8 + T and CD103 + CD8 + T cell-mediated anti-tumor response within the tumor microenvironment (TME) of human CRC. Specifically, RUNXs were significantly differentially expressed between tumor and normal tissues in CRC. Patients with a greater proportion of infiltrating CD8 + RUNX1 + , CD103 + CD8 + RUNX1 + , CD8 + RUNX2 + , CD103 + CD8 + RUNX2 + , CD8 + RUNX3 + , or CD103 + CD8 + RUNX3 + T cells demonstrated improved outcomes compared to those with lower proportions. Additionally, the proportions of infiltrating CD8 + RUNX1 + T and CD8 + RUNX3 + T cells may serve as valuable prognostic predictors for CRC patients, independent of other clinicopathological factors. Moreover, further bioinformatic analysis conducted utilizing the TISIDB and TIMER platforms demonstrated significant associations between the members of the RUNX family and immune-infiltrating cells, specifically diverse subpopulations of CD8 + TILs. Our study of human colorectal cancer tissue microarray (TMA) also revealed positive and statistically significant correlations between the expressions of RUNX1, RUNX2, and RUNX3 in both CD8 + T cells and CD103 + CD8 + T cells. Our study comprehensively revealed the varied expressions and prognostic importance of the RUNX family in human colorectal cancer tissues. It underscored their potential as vital biomarkers for prognostic evaluation in colorectal cancer patients and as promising targets for immunotherapy in treating this disease.

The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions. The transcription factor RUNX3 plays a key role in the restriction point of cell cycle. Here the authors showed that RUNX3 binds and opens chromatin structure of restriction point associated genes, by sequential recruitment of chromatin remodeling complex, transcription complex and cell cycle regulators.

Hypercholesterolemia is a leading cause of various cardiovascular diseases (CVDs). 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (Hmgcr) is the rate-limiting enzyme in the cholesterol biosynthesis pathway. Previous studies investigated the regulation of Hmgcr expression under various pathophysiological conditions. However, its expression under hypoxia, an important player in the pathogenesis of CVD, is poorly understood. The present study investigated the hepatic expression of Hmgcr and Hif-1α in Spontaneously hypertensive rats [SHR] and its normotensive control, Wistar Kyoto [WKY] rats. Interestingly, hepatic Hmgcr expression was diminished while Hif-1α expression was elevated in SHR. In cultured rat liver cells, the Hmgcr promoter activity/transcript/protein and intracellular cholesterol levels were diminished after hypoxia treatment. Further, while Hif-1α /Runx3 transcript and protein levels were enhanced, Srebf levels decreased upon hypoxia. Knock-down of Hif-1α abrogated the hypoxia-mediated effect on Hmgcr, intracellular cholesterol levels, and the expression of Srebf and Runx3. Chromatin immunoprecipitation (ChIP) assays showed binding of Hif-1α to both endogenous SHR- and WKY-Hmgcr/Srebf/Runx3 domains with similar promoter occupancies. However, differential binding of Hif-1α to Srebf and Runx3 promoter domains were observed from ChIP assay. While HIF-1α showed a negative correlation with HMGCR/SREBF transcript levels, it correlated positively with RUNX3. Additionally, ChIP assays demonstrated differential binding of Srebf and Runx3 to SHR/WKY-Hmgcr promoter domains upon hypoxic stress. Taken together, this study elucidates the regulatory role of Hif-1α in modulating Hmgcr expression and intracellular cholesterol levels via Srebf and Runx3 under hypoxic stress. These findings provide new mechanistic insights underlying cholesterol homeostasis under hypoxia.

Memory CD8 + T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8 + T cell innate memory program. T box transcription factor Eomesodermin (EOMES) is induced when naïve T cells are converted to innate memory T cells in response to cytokines. Here the authors show that EOMES is recruited to RUNX3-bound enhancers and interacts with BRG1 during innate memory T cell formation.

NK cells are cytotoxic innate immune cells involved in antitumor immunity, and they provide a treatment option for patients with acute myeloid leukemia (AML). In this issue of the JCI, Cubitt et al. investigated the role of CD8α, a coreceptor present on approximately 40% of human NK cells. IL-15 stimulation of CD8α- NK cells induced CD8α expression via the RUNX3 transcription factor, driving formation of a unique induced CD8α (iCD8α+) population. iCD8α+ NK cells displayed higher proliferation, metabolic activity, and antitumor cytotoxic function compared with preexisting CD8α+ and CD8α- subsets. Therefore, CD8α expression can be used to define a potential dynamic spectrum of NK cell expansion and function. Because these cells exhibit enhanced tumor control, they may be used to improve in NK cell therapies for patients with AML.

Runt-related transcription factor 3 (RUNX3) is a well-documented tumour suppressor that is frequently inactivated in gastric cancer. Here, we define a novel mechanism by which RUNX3 exerts its tumour suppressor activity involving the TEAD–YAP complex, a potent positive regulator of proliferative genes. We report that the TEAD–YAP complex is not only frequently hyperactivated in liver and breast cancer, but also confers a strong oncogenic activity in gastric epithelial cells. The increased expression of TEAD–YAP in tumour tissues significantly correlates with poorer overall survival of gastric cancer patients. Strikingly, RUNX3 physically interacts with the N-terminal region of TEAD through its Runt domain. This interaction markedly reduces the DNA-binding ability of TEAD that attenuates the downstream signalling of TEAD–YAP complex. Mutation of RUNX3 at Arginine 122 to Cysteine, which was previously identified in gastric cancer, impairs the interaction between RUNX3 and TEAD. Our data reveal that RUNX3 acts as a tumour suppressor by negatively regulating the TEAD–YAP oncogenic complex in gastric carcinogenesis.