Haengseok Song - Academia.edu (original) (raw)

Papers by Haengseok Song

Nature Communications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. ... more Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1d/d ectopic lesions showed P4 resistance, which was rescued...

Additional file 3: Figure S2. Optimization of E2 concentration for hematopoiesis.

Additional file 1: Figure S1. Temporal change of ER-alpha during hiPSC-derived hematopoietic deve... more Additional file 1: Figure S1. Temporal change of ER-alpha during hiPSC-derived hematopoietic development.

Reproductive Sciences, 2021

Previous studies have reported that the mitochondrial DNA (mtDNA) contents of cumulus cells (CCs)... more Previous studies have reported that the mitochondrial DNA (mtDNA) contents of cumulus cells (CCs) in ovarian follicular fluid are correlated with embryo quality. Quantification of mtDNA CCs has been suggested as a biomarker of embryo viability. The aim of this study was to determine the relationship between mitochondrial DNA (mtDNA)/genomic DNA (gDNA) ratio in CCs and IVF outcomes such as fertilization rates and embryo quality in infertile women. This is an observational study on 144 cumulus-oocyte complexes obtained from 144 patients undergoing IVF-intracytoplasmic sperm injection (ICSI) at a single fertility center. The CCs in ovarian follicular fluid from patients undergoing IVF-ICSI were collected by ovum pick-up. A relative copy number quantification was used to determine mtDNA/gDNA ratio. Quantitative real–time PCR for various markers (β2M and mtMinArc gene) was used to determine average mtDNA/gDNA ratio of CCs. Investigation of the correlation between mtDNA/gDNA ratio in CCs and IVF outcomes showed no statistically significant correlation between the mtDNA/gDNA ratio in CCs and fertilization rates. However, mtDNA/gDNA ratio and embryo quality showed a statistically significant positive correlation. A significantly higher mtDNA/gDNA ratio was observed in the good quality embryo group compared with the poor quality embryo group (P < 0.05). In addition, the mtDNA/gDNA ratio showed negative correlation with the patient’s age (correlation coefficient= −0.228, P < 0.05). Results of this study demonstrate a negative correlation of mtDNA/gDNA ratio in CCs with patient’s age, and a low copy number of mtDNA in CCs may have adverse effects on embryo quality in IVF cycles. These results suggest that the ratio of mtDNA/gDNA in CCs may serve as a biomarker in predicting IVF outcomes.

Autophagy, 2020

The uterus undergoes vascular changes during the reproductive cycle and pregnancy. Steroid hormon... more The uterus undergoes vascular changes during the reproductive cycle and pregnancy. Steroid hormone deprivation induces macroautophagy/autophagy in major uterine cell types. Herein, we explored the functions of uterine autophagy using the Amhr2-Cre-driven atg7 deletion model. Deletion of Atg7 was confirmed by functional deficit of autophagy in uterine stromal, myometrial, and vascular smooth muscle cells, but not in endothelial cells. atg7 d/d uteri exhibited enhanced stromal edema accompanied by dilation of blood vessels. Ovariectomized atg7 d/d uteri showed decreased expression of endothelial junction-related proteins, such as CTNNB1/beta-catenin, with increased vascular permeability, and increased expression of VEGFA and NOS1. Nitric oxide (NO) was shown to mediate VEGFA-induced vascular permeability by targeting CTNNB1. NO involvement in maintaining endothelial junctional stability in atg7 d/d uteri was confirmed by the reduction in extravasation following treatment with a NOS inhibitor. We also showed that atg7 d/d uterine phenotype improved the fetal weight:placental weight ratio, which is one of the indicators of assessing the status of preeclampsia. We showed that autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through the deregulation of VEGFA, NOS1, and CTNNB1.

Tissue Engineering and Regenerative Medicine, 2019

BACKROUND: CRISPR/Cpf1 is a class II, type V RNA-guided endonuclease that is distinct from the ty... more BACKROUND: CRISPR/Cpf1 is a class II, type V RNA-guided endonuclease that is distinct from the type II CRISPR/Cas9 nuclease, widely used for genome editing. Cpf1 is a smaller and simpler endonuclease than Cas9, overcoming some limitations of the CRISPR/Cas9 system. The applications of CRISPR to rodent embryos for the production of knockout (KO) mice have been achieved mainly by microinjection, which requires heavily-equipped instruments with skillful hands. Here, we evaluated the genome editing efficiency between Cpf1/mRNA and Cpf1/ribonuclear protein (RNP) in mouse embryos, and established an easy, fast, and technically less demanding method to produce KO mice using electroporation of the Cfp1/RNP system. METHODS: The efficiency of electroporation-based delivery of AsCpf1/mRNA and AsCpf1/RNP to target exon 3 of leukemia inhibitory factor (Lif) into mouse zygotes was evaluated. Embryos that developed to the two-cell stage after zygote electroporation were transferred into the oviducts of surrogate mothers to produce AsCpf1-mediated LIF KO mice. The genome editing efficiency of blastocysts and pups was tested using the T7E1 assay and/or DNA sequencing. Congenital abnormalities and reproductive phenotypes in LIF KO mice produced by electroporation with AsCpf1/RNP were examined. RESULTS: Survival and two-cell development of electroporated zygotes were comparable between the AsCpf1/mRNA and AsCpf1/RNP groups, whereas genome editing efficiency was relatively higher in the AsCpf1/RNP group (13.3% vs 18.1% at blastocyst and 33.3% vs 45.5% at offspring), respectively. Two mouse lines with a frameshift mutation in exon 3 of the Lif gene were established from the AsCpf1/RNP group. All congenital abnormalities of LIF KO mice produced by AsCpf1/RNP electroporation were observed. AsCpf1-mediated LIF KO mice showed postnatal growth retardation and implantation failure, both of which are major phenotypes of LIF KO mice generated by conventional gene targeting. CONCLUSION: Electroporation of AsCpf1/RNP at the zygote stage is an efficient genome editing method to produce KO mice. Keywords CRISPR/AsCpf1 Á Electroporation Á AsCpf1/RNP Á Gene targeting Á Embryo Á LIF Yeon Sun Kim and Gyeong Ryeong Kim are equally contributed to this work.

Biomaterials, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Molecular and cellular endocrinology, Jan 7, 2017

Dexamethasone-induced RAS-related protein 1 (RASD1) is a signaling protein that is involved in va... more Dexamethasone-induced RAS-related protein 1 (RASD1) is a signaling protein that is involved in various cellular processes. In a previous study, we found that RASD1 expression was down-regulated in the uterine endometrium of repeated implantation failure patients. The study aim was to determine whether RASD1 is expressed in the endometrium of mouse uterus and how it is regulated by steroid hormones during the estrous cycle. In this study, we investigated RASD1 expression and regulation in an ovariectomized female mouse model. Rasd1 mRNA was highly expressed in mouse reproductive tissues, including the uterus. Rasd1 expression was detected exclusively in the endometrial epithelium at the proestrus stage of the estrous cycle. Rasd1 expression in uteri increased with administration of estradiol, but not progesterone. Its expression was rapidly induced within 2 h after E2 treatment. Pretreatment with ICI 182,780, an estrogen receptor antagonist, reduced RASD1 protein expression. In addit...

MII oocytes were vitrified and stored in LN2 for 4 weeks. After t... more MII oocytes were vitrified and stored in LN2 for 4 weeks. After thawing, oocytes were subjected to immunofluorescence staining with anti-mDia2 and anti-pericentrin antibodies. Overlapped distribution of mDia2 and pericentrin generates yellow fluorescence (overlay). DNA is counter-stained with TO-PRO-3-iodide. Green, mDia2; red, pericentrin; blue, DNA. The bottom panel shows the magnified region of the chromosome-spindle complex. DNA is not visible in high magnification images because it is out of focus.</p

Biochemical and Biophysical Research Communications, 2016

The sine oculis homeobox 1 (SIX1) is a member of the Six gene family. SIX1 is involved in tissue ... more The sine oculis homeobox 1 (SIX1) is a member of the Six gene family. SIX1 is involved in tissue development by regulating proliferation, apoptosis, and differentiation. However, function of SIX1 in the uterus remains unknown. Here, we found that Six1 expression is regulated along the estrous cycle in mouse uterus. Six1 expression was significantly increased at estrus stage and decreased at the rest of stages. SIX1 is detected in the luminal and glandular epithelium of uterine endometrium at the estrus stage. Estrogen injection increased Six1 expression in the ovariectomized mouse uterus, whereas progesterone had no effect on its expression. Estrogen receptor antagonist inhibited estrogen-induced Six1 expression. Our findings imply that SIX1 may play a role as an important regulator to orchestrate the dynamic of uterine endometrium in response to estrogen level during the estrous cycle. These results will give us a better understanding of uterine biology.

Cancer Research, 2014

Purpose: Circulating endothelial cells (CECs) have been widely used as a prognostic biomarker and... more Purpose: Circulating endothelial cells (CECs) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biological roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells. Experimental Design: The frequency of representative CEC subsets (i.e., CD45-/CD31+, CD45-/CD31+/CD146+, CD45-/CD31+/CD105+) was analyzed in the peripheral blood of gynecological cancer patients (n=56) and healthy volunteers (n=44). CD45-/CD31+ cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry. Results: CD45-/CD31+/CD105+ cells were signific...

Molecular and Cellular Endocrinology, 2015

Aimp1 is known as a multifunctional cytokine in various cellular events. Recent study showed Aimp... more Aimp1 is known as a multifunctional cytokine in various cellular events. Recent study showed Aimp1 is localized in glandular epithelial, endothelial, and stromal cells in functionalis and basalis layers of the endometrium. However, the regulatory mechanism of Aimp1 in the uterus remains unknown. In the present study, we found that Aimp1 is expressed in the mouse uterus. Aimp1 transcripts were decreased at diestrus stage. However, the level of Aimp1 protein was significantly increased in the luminal epithelium in the uterine endometrium at estrus stage during the estrous cycle. We found that treatment of estrogen increased the expression of Aimp1 in the uterus in ovarectomized mice. We identified one estrogen receptor binding element (ERE) on mouse Aimp1 promoter. The activity of Aimp1 promoter was increased with estrogen treatment. Our findings indicate that Aimp1 might act as an important regulator to remodel the uterine endometrium and its expression might be regulated by estrogen during the estrous cycle. This will give us better understanding of the dynamic change of uterine remodeling during the estrous cycle.

Reproductive Toxicology, 2014

Coordinate actions of ovarian estrogen (E2) and progesterone (P4) via their own receptors are cri... more Coordinate actions of ovarian estrogen (E2) and progesterone (P4) via their own receptors are critical for establishing uterine receptivity for embryo implantation in the uterus. E2 regulates expression of an array of genes to mediate its major actions on heterogeneous uterine cell types. Here we have investigated regulatory mechanism(s) of E2 and bisphenol A (BPA), an endocrine disruptor with potent estrogenic activity on expression of early growth response 1 (Egr1), a zinc finger transcription factor that regulates cell growth, differentiation and apoptosis in the uterus. Egr1 was rapidly and transiently induced by E2 and BPA mainly in stromal cells via nuclear estrogen receptor (ER)-ERK1/2 pathway. ICI 182,780, an ER antagonist, effectively inhibited their actions on EGR1 expression following ERK1/2 phosphorylation. Administration of pharmacological inhibitors for ERK1/2, but not AKT significantly blocked EGR1 expression induced by E2 and BPA. P4 effectively dampened action(s) of E2 and BPA on Egr1 expression via nuclear progesterone receptor. Its antagonistic effects were partially interfered with RU486 pretreatment. Interestingly, EGR1 is specifically induced in stromal cells surrounding implanting blastocyst. Collectively, our results show that through nuclear ER-dependent ERK1/2 phosphorylation, not only E2 but also endocrine disruptors with estrogenic activity such as BPA rapidly and transiently induce Egr1 which may be important for embryo implantation and decidualization in mouse uterus.

Reproductive Toxicology, 2010

We have investigated the potential actions of E 2 and endocrine disruptors (EDs) with estrogenic ... more We have investigated the potential actions of E 2 and endocrine disruptors (EDs) with estrogenic activity, such as bisphenol A, on the regulation of the Sprr2 family of genes in the mouse uterus using real-time RT-PCR, RT-PCR and Western blotting. Most members of Sprr2 genes that are induced by E 2 , such as Sprr2a, 2b and 2e, showed E 2 dose-dependent increase at mRNA levels. Sprr2 expression was considerably reduced by pretreatment with ICI 182,780, an antagonist for nuclear estrogen receptors. Progesterone moderately dampened E 2-induced Sprr2 expression. Furthermore, EDs comparably induced the expression of Sprr2 genes in a dose-dependent manner and EDs-induced Sprr2 expression was similarly modulated by ICI 182,780 and progesterone, strongly suggesting that they are, indeed, an estrogen-responsive gene family. Collectively, dose-dependent induction of Sprr2 genes by estrogen and EDs is primarily mediated via the genomic actions of estrogen signaling in the uterus, but not in other reproductive tracts, in mice.

Fertility and Sterility, 2009

Objective: To evaluate objectively whether poor sperm quality affects sequential events from fert... more Objective: To evaluate objectively whether poor sperm quality affects sequential events from fertilization to delivery in fresh intracytoplasmic sperm injection (ICSI) and subsequent frozen-thawed embryo transfer (ET) cycles. Design: Retrospective study. Setting: University-based centers for reproductive medicine. Patient(s): For unbiased comparison, 206 cycles were chosen from 1,999 cycles of patients who underwent ICSI-ET and/or subsequent frozen-thawed ET. Cycles met the following criteria: day 3 ET; female age, <40 y; number of retrieved oocytes, R5; no split insemination; and no female factors but tubal factor. Intervention(s): None. Main Outcome Measure(s): The rates of fertilization, embryo implantation, clinical pregnancy, and delivery and sequential embryonic score (SES) were compared between normal-spermatogenesis patients (NSPs) and defectivespermatogenesis patients (DSPs). Result(s): Although sum SES, mean SES, and top SES of transferred embryos on day 3 were similar between NSPs and DSPs, the rates of implantation, clinical pregnancy, and delivery of NSPs were significantly higher than those of DSPs. Furthermore, subsequent ET cycles with frozen-thawed embryos in NSPs and DSPs who failed to achieve pregnancy in their fresh cycles showed that rates of implantation and clinical pregnancy also were significantly lower in DSPs. Conclusion(s): Quality of sperm may influence embryo implantation and subsequent pregnancy outcomes without impairment of embryo quality.

Korean Journal of Biological Sciences, 1998

In this study, we have examined the role of cAMP in gap junctional communication (GJC) in preimpl... more In this study, we have examined the role of cAMP in gap junctional communication (GJC) in preimplantation mouse embryos. GJC was monitored by Lucifer Yellow (LY) injected into one blastomere of compacted embryos. The speed of GJC was defined as the time taken for the last blastomere of the embryo to become visibly fluorescent. The median time for 8‐cell embryos

Cell Proliferation, 2021

The female reproductive tract comprises several different cell types. Using three representative ... more The female reproductive tract comprises several different cell types. Using three representative Cre systems, we comparatively analysed the phenotypes of Dgcr8 conditional knockout (cKO) mice to understand the function of Dgcr8, involved in canonical microRNA biogenesis, in the female reproductive tract.