This gene shows sequence homology to the fly gene RUNT, a transcriptional factor.
This gene was found to be regulated by gonadotropins in DNA arrays. YAP in the Hippo signaling pathway targets transcription factor partners—including RUNX.
NCBI Summary:
Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Ovulation, Steroid metabolism
Comment
Activation of Steroidogenesis, Anti-Apoptotic Activity, and Proliferation in Porcine Granulosa Cells by RUNX1 Is Negatively Regulated by H3K27me3 Transcriptional Repression. Zhong Y et al. (2020) H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1) influences granulosa cells' growth and ovulation. This research uses ELISA, flow cytometry, EDU, ChIP-PCR, WB and qPCR to investigate steroidogenesis, cell apoptosis, and the proliferation effect of RUNX1 in porcine granulosa cells (pGCs) as regulated by H3K27me3. Decreased H3K27me3 stimulates the expression of steroidogenesis-related genes, including CYP11A1, PTGS2, and STAR, as well as prostaglandin. H3K27me3 transcriptionally represses RUNX1 here, whereas RUNX1 acts as an activator of FSHR, CYP11A1, and CYP19A1, promoting the production of androgen, estrogen, and prostaglandin, as well as increasing anti-apoptotic and cell proliferation activity, but decreasing progesterone. Both the complementary recovery of the H3K27me3 antagonist with the siRUNX1 signal, and the H3K27me3 agonist with the RUNX1 signal to maintain RUNX1 lead to the activation of CYP19A1, ER1, HSD17β4, and STAR here. Androgen and prostaglandin are significantly repressed but progesterone is markedly increased with the antagonist and siRUNX1. Prostaglandin is significantly promoted with the agonist and RUNX1. Furthermore, H3K27me3-RUNX1 affects the anti-apoptotic activity and stimulation of proliferation in pGCs. The present work verifies the transcriptional suppression of RUNX1 by H3K27me3 during antral follicular development and maturation, which determines the levels of hormone synthesis and cell apoptosis and proliferation in the pGC microenvironment.//////////////////
RUNX1 Transcription Factor Regulates LH-induced Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) Expression in Rat Periovulatory Granulosa Cells. Liu J et al. RUNX1, a transcription factor, is transiently induced by the LH surge and regulates gene expression in periovulatory granulosa cells. Potential binding sites for RUNX are present in the 5'-flanking region of the Ptgs2 (prostaglandin-endoperoxide synthase 2) gene. Periovulatory Ptgs2 expression is essential for ovulation. In the present study, we investigated the role of RUNX1 in mediating the LH-induced expression of Ptgs2 in periovulatory granulosa cells. We first determined whether the suppression of Runx1 expression or activity affects Ptgs2 expression using cultured preovulatory granulosa cells isolated from immature rat ovaries primed with PMSG for 48 h. Knockdown of hCG-induced Runx1 expression by siRNA or inhibition of endogenous RUNX activities by dominant-negative RUNX (DNRUNX) decreased hCG or agonist-stimulated Ptgs2 expression and transcriptional activity of Ptgs2 promoter reporter constructs. Results from chromatin immunoprecipitation assays revealed in vivo binding of endogenous RUNX1 to the Ptgs2 promoter region in rat periovulatory granulosa cells. Direct binding of RUNX1 to two RUNX-binding motifs in the Ptgs2 promoter region was confirmed by electrophoretic mobility shift assays. The mutation of these two binding motifs resulted in decreased transcriptional activity of Ptgs2 promoter reporter constructs in preovulatory granulosa cells. Taken together, these findings provide experimental evidence that the LH-dependent induction of Ptgs2 expression results, in part, from RUNX1-mediated transactivation of the Ptgs2 promoter. The results of the present study assign potential significance for LH-induced RUNX1 in the ovulatory process via regulating Ptgs2 gene expression.
Expression regulated by
LH, WT1
Comment
Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Naillat F et al. (2015) The indifferent mammalian embryonic gonad generates an ovary or testis, but the factors involved are still poorly known. The Wnt-4 signal represents one critical female determinant, since its absence leads to partial female-to-male sex reversal in mouse, but its signalling is as well implicated in the testis development. We used the Wnt-4-deficient mouse as a model to identify candidate gonadogenesis genes, and found that the Notum, Phlda2, Runx-1 and Msx1 genes are typical of the wild-type ovary and the Osr2, Dach2, Pitx2 and Tacr3 genes of the testis. Strikingly, the expression of these latter genes becomes reversed in the Wnt-4 knock-out ovary, suggesting a role in ovarian development. We identified the transcription factor Runx-1 as a Wnt-4 signalling target gene, since it is expressed in the ovary and is reduced upon Wnt-4 knock-out. Consistent with this, introduction of the Wnt-4 signal into early ovary cells ex vivo induces Runx-1 expression, while conversely Wnt-4 expression is down-regulated in the absence of Runx-1. We conclude that the Runx-1 gene can be a Wnt-4 signalling target, and that Runx-1 and Wnt-4 are mutually interdependent in their expression. The changes in gene expression due to the absence of Wnt-4 in gonads reflect the sexually dimorphic role of this signal and its complex gene network in mammalian gonad development.//////////////////
Periovulatory Expression of Hyaluronan and Proteoglycan Link Protein 1 (Hapln1) in the Rat Ovary: Hormonal Regulation and Potential Function. Liu J et al. Periovulatory follicular matrix plays an important role in cumulus-oocyte complex (COC) expansion, ovulation, and luteal formation. Hyaluronan and proteoglycan link protein 1 (HAPLN1), a component of follicular matrix, was shown to enhance COC expansion in vitro. However, the regulatory mechanisms of periovulatory expression of Hapln1 and its role in periovulatory granulosa cells have not been elucidated. We first determined the periovulatory expression pattern of Hapln1 using pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-primed immature rat ovaries. Hapln1 expression was transiently induced both in intact ovaries and granulosa cells at 8 h and 12 h after hCG injection. This in vivo expression of Hapln1 was recapitulated by culturing preovulatory granulosa cells with hCG. The stimulatory effect of hCG was blocked by inhibition of protein kinase A, phosphatidylinositol-dependent kinase, p38 MAPK, epidermal growth factor signaling, and prostaglandin synthesis, revealing key mediators involved in LH-induced Hapln1 expression. In addition, knockdown of Runx1 and Runx2 expression by small interfering RNA or inhibition of RUNX activities by dominant-negative RUNX decreased hCG or agonist-induced Hapln1 expression. Chromatin immunoprecipitation assays verified the in vivo binding of RUNX1 and RUNX2 to the Hapln1 promoter in periovulatory granulosa cells. Luciferase reporter assays revealed that mutation of the RUNX binding sites completely obliterated the agonist-induced activity of the Hapln1 promoter. These data conclusively identified RUNX proteins as the crucial transcription regulators for LH-induced Hapln1 expression. Functionally, treatment with HAPLN1 increased the viability of cultured granulosa cells and decreased the number of the cells undergoing apoptosis, whereas knockdown of Hapln1 expression decreased granulosa cells viability. This novel finding indicates that HAPLN1 may promote periovulatory granulosa cell survival, which would facilitate their differentiation into luteal cells.
Development and Application of a Rat Ovarian Gene Expression Database (rOGED) Jo M, et al 2004 . The pituitary gonadotropins play a key role in follicular development and ovulation through the induction of specific genes. To identify these genes, we have constructed a genome-wide rat ovarian gene expression database (rOGED). The database was constructed from total RNA isolated from intact ovaries, granulosa cells, or residual ovarian tissues collected from immature PMSG/hCG-treated rats at 0 (no PMSG), 12, and 48 h post-PMSG, as well as 6 and 12 h post-hCG. The total RNA was used for DNA microarray analysis using Affymetrix Rat Expression Arrays 230A and B. The microarray data were compiled and used for display of individual gene expression profiles through specially developed software. The final rOGED provides immediate analysis of temporal gene expression profiles for over 28,000 genes in intact ovaries, granulosa cells, and residual ovarian tissue during follicular growth and the preovulatory period. The accuracy of the rOGED was validated against the gene profiles for over 20 known genes. The utility of the rOGED was demonstrated by identifying six genes which have not been described in the rat periovulatory ovary. The mRNA expression patterns and cellular localization for each of these six genes, estrogen sulfotransferase, synaptosomal-associated protein 25 kDa, runt related transcription factor, calgranulin B, alpha1-macroglobulin, and MAP kinase phosphotase-3, were confirmed by Northern blot analyses and in situ hybridization, respectively. The current findings demonstrate that the rOGED can be used as an instant reference for ovarian gene expression profiles, as well as a reliable resource for identifying important yet, to date, unknown ovarian genes.
Ovarian localization
Granulosa, Theca
Comment
[P1-243] Identification and Characterization of Five Genes Induced by hCG Administration during the Preovulatory Period in the Rat Ovary.
(Endocrine society 2004)
Misung Jo, Mary C Gieske, Sarah E Wheeler, Charles E Payne, Chemyong Ko, Thomas E Curry, Jr. Ob and Gyn, Univ of Kentucky, Lexington, KY; Clin Scis, Univ of Kentucky, Lexington, KY
The LH surge initiates the ovulatory process by triggering a series of biochemical and molecular events that induce the spatiotemporal expression of specific genes. In the present study, we utilized a newly developed rat ovarian gene expression database (rOGED) to identify unknown genes involved in the ovulatory process. Five genes that showed elevated levels of mRNA expression after hCG treatment in rOGED were selected. These genes included mitogen-activated protein kinase phosphotase-3 (MKP-3), runt related transcription factor (Runx 1), calgranulin B, 1-macroglobulin, and synaptosome-associated protein 25 kDa (Snap 25). To confirm and characterize the spatiotemporal expression pattern of these genes during the periovulatory period, immature rats were injected with PMSG; 48 h later hCG was administered. Ovaries were collected at 0 (48 h post-eCG), 6, 12, and 24 h post-hCG. Northern blots revealed dramatic, yet transient increases in levels of mRNA for Runx 1, calgranulin B, MKP-3, and 1-macroglobulin at 6 h post-hCG, which are consistent with the profiles seen in rOGED. Two transcripts of the Snap 25 gene were detected, which were expressed differentially after hCG injection. In situ hybridization showed a distinct localization pattern of expression of these genes. High expression of both Runx 1 and MKP-3 was localized to the granulosa cell layer of preovulatory follicles at 6 and 12 h post-hCG, but the expression was also detected in the theca layer at 6 h post-hCG. MKP-3 can inactivate ERKs while Runx 1 is involved in the cell differentiation/ proliferation process. Snap 25 mRNA was localized to granulosa cells of preovulatory follicles and the theca layer at 12 h post-hCG. Snap 25 is a key component of SNARE proteins required for intracellular membrane fusion events during exocytosis. 1-Macroglobulin can inhibit a broad spectrum of proteases and was localized only to the theca layer at 6 h post-hCG. Calgranulin B mRNA was localized to cells scattered in the interstitial and stroma layer of ovaries obtained at 6 h and 12 h post-hCG, but not to follicular cells. Calgranulin B is highly expressed in neutrophils and monocytes that are found in a variety of inflammatory conditions. The fact that the ovulatory hCG stimulus induces dramatic, yet transient increases in levels of mRNA for these genes in a cell-type specific manner suggests that the expression of each of these genes may be important for successful ovulation.
Follicle stages
Antral, Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: embryonic lethal Comment: An unexpected role for IL-3 in the embryonic development of hematopoietic stem cells. Robin C et al. (2006) Cytokines are important in adult hematopoiesis, yet their function in embryonic hematopoiesis has been largely unexplored. During development, hematopoietic stem cells (HSCs) are found in the aorta-gonad-mesonephros (AGM) region, yolk sac (YS), and placenta and require the Runx1 transcription factor for their normal generation. Since IL-3 is a Runx1 target and this cytokine acts on adult hematopoietic cells, we examined whether IL-3 affects HSCs in the mouse embryo. Using Runx1 haploinsufficient mice, we show that IL-3 amplifies HSCs from E11 AGM, YS, and placenta. Moreover, we show that IL-3 mutant embryos are deficient in HSCs and that IL-3 reveals the presence of HSCs in the AGM and YS prior to the stage at which HSCs are normally detected. Thus, our studies support an unexpected role for IL-3 during development and strongly suggest that IL-3 functions as a proliferation and/or survival factor for the earliest HSCs in the embryo.//////////////////