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Core Binding Factor-? Knockdown Alters Ovarian Gene Expression and Function in the Mouse.

ABSTRACT: Core binding factor (CBF) is a heterodimeric transcription factor complex composed of a DNA-binding subunit, one of three runt-related transcription factor (RUNX) factors, and a non-DNA binding subunit, CBF?. CBF? is critical for DNA binding and stability of the CBF transcription factor complex. In the ovary, the LH surge increases the expression of Runx1 and Runx2 in periovulatory follicles, implicating a role for CBFs in the periovulatory process. The present study investigated the functional significance of CBFs (RUNX1/CBF? and RUNX2/CBF?) in the ovary by examining the ovarian phenotype of granulosa cell-specific CBF? knockdown mice; CBF? f/f * Cyp19 cre. The mutant female mice exhibited significant reductions in fertility, with smaller litter sizes, decreased progesterone during gestation, and fewer cumulus oocyte complexes collected after an induced superovulation. RNA sequencing and transcriptome assembly revealed altered expression of more than 200 mRNA transcripts in the granulosa cells of Cbfb knockdown mice after human chorionic gonadotropin stimulation in vitro. Among the affected transcripts are known regulators of ovulation and luteinization including Sfrp4, Sgk1, Lhcgr, Prlr, Wnt4, and Edn2 as well as many genes not yet characterized in the ovary. Cbf? knockdown mice also exhibited decreased expression of key genes within the corpora lutea and morphological changes in the ovarian structure, including the presence of large antral follicles well into the luteal phase. Overall, these data suggest a role for CBFs as significant regulators of gene expression, ovulatory processes, and luteal development in the ovary.

SUBMITTER: Wilson K

PROVIDER: S-EPMC4926233 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Core Binding Factor-β Knockdown Alters Ovarian Gene Expression and Function in the Mouse.

Wilson Kalin K Park Jiyeon J Curry Thomas E TE Mishra Birendra B Gossen Jan J Taniuchi Ichiro I Jo Misung M

Molecular endocrinology (Baltimore, Md.) 20160513 7

Core binding factor (CBF) is a heterodimeric transcription factor complex composed of a DNA-binding subunit, one of three runt-related transcription factor (RUNX) factors, and a non-DNA binding subunit, CBFβ. CBFβ is critical for DNA binding and stability of the CBF transcription factor complex. In the ovary, the LH surge increases the expression of Runx1 and Runx2 in periovulatory follicles, implicating a role for CBFs in the periovulatory process. The present study investigated the functional ...[more]

PMID: 27176614

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Project description:BackgroundThis study aimed to investigate the effect of abnormal Core binding factor-β expression on proliferation, differentiation and apoptosis of chondrocytes, and elucidate the relationship between Core binding factor-β and osteoarthritis-related markers and degenerative joint disease.MethodsCartilage tissues, from healthy subjects and patients with osteoarthritis, were collected for histology and expression of Core binding factor-β, MMP-13, IL-1β, COMP, and YKL-40. Human articular chondrocytes were cultured in vitro, and a viral vector was constructed to regulate cellular Core binding factor-β expression. Cellular proliferation and apoptosis were observed, and osteoarthritis-related inflammatory factor expression and cartilage metabolite synthesis assayed.ResultsHuman osteoarthritis lesions had disordered cartilage structure and cellular arrangement, and increased emptying of cartilage lacunae. Normal cell counts were significantly reduced, cartilage extracellular matrix was obviously damaged, and type II collagen expression was significantly decreased. Core binding factor-β was highly expressed in the osteoarthritis cartilage (p < 0.001), and MMP-13, IL-1β, COMP and YKL-40 expression were greater than found in normal cartilage (p < 0.001). Cellular proliferation in the Core binding factor-β high-expression group was reduced and the total apoptosis rate was increased (p < 0.05), while the opposite was found in the Core binding factor-β inhibition group (p < 0.01). Compared with normal chondrocytes, high Core binding factor-β expression (Osteoarthritis and CBFB/pCDH groups) was associated with significantly increased MMP13, IL-1β, COMP and YKL-40 protein expression (p < 0.01), while Core binding factor-β inhibition (CBFB/pLKO.1 group) was associated with significantly decreased COMP, MMP13, IL-1β and YKL-40 expression in osteoarthritis cells (p < 0.001).ConclusionsAbnormal Core binding factor-β expression might play an upstream regulatory role in mediating abnormal chondrocyte apoptosis and the inflammatory response. On inhibiting Core binding factor-β expression, a delay in cartilage degeneration was expected.Trial registrationThe study was registered for clinical trials in ChiCTR: ChiCTR1800017066 (Reg. Date-2018/7/10).

Project description:Fibromodulin (FMOD) is a small leucine-rich proteoglycan required for scarless fetal cutaneous wound repair. Interestingly, increased FMOD levels have been correlated with decreased transforming growth factor (TGF)-β1 expression in multiple fetal and adult rodent models. Our previous studies demonstrated that FMOD-deficiency in adult animals results in delayed wound closure and increased scar size accompanied by loose package collagen fiber networks with increased fibril diameter. In addition, we found that FMOD modulates in vitro expression and activities of TGF-β ligands in an isoform-specific manner. In this study, temporospatial expression profiles of TGF-β ligands and receptors in FMOD-null and wild-type (WT) mice were compared by immunohistochemical staining and quantitative reverse transcriptase-polymerase chain reaction using a full-thickness, primary intention wound closure model. During the inflammatory stage, elevated inflammatory infiltration accompanied by increased type I TGF-β receptor levels in individual inflammatory cells was observed in FMOD-null wounds. This increased inflammation was correlated with accelerated epithelial migration during the proliferative stage. On the other hand, significantly more robust expression of TGF-β3 and TGF-β receptors in FMOD-null wounds during the proliferative stage was associated with delayed dermal cell migration and proliferation, which led to postponed granulation tissue formation and wound closure and increased scar size. Compared with WT controls, expression of TGF-β ligands and receptors by FMOD-null dermal cells was markedly reduced during the remodeling stage, which may have contributed to the declined collagen synthesis capability and unordinary collagen architecture. Taken together, this study demonstrates that a single missing gene, FMOD, leads to conspicuous alternations in TGF-β ligand and receptor expression at all stages of wound repair in various cell types. Therefore, FMOD critically coordinates temporospatial distribution of TGF-β ligands and receptors in vivo, suggesting that FMOD modulates TGF-β bioactivity in a complex way beyond simple physical binding to promote proper wound healing.

Dataset Information

Core Binding Factor-? Knockdown Alters Ovarian Gene Expression and Function in the Mouse.

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Core Binding Factor-β Knockdown Alters Ovarian Gene Expression and Function in the Mouse.

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