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| Open AccessA common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis
Authors show that a common SNP upregulates endometrial Wnt4 expression and proimplantation genes in mouse proestrus and estrus. They suggest that this increases uterine permissiveness to embryo invasion, while decreasing resistance to invasion in reproductive cancers and endometriosis.
- Mihaela Pavličev
- , Caitlin E. McDonough-Goldstein
- & Louis Muglia
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Article
| Open AccessMolecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Investigating the genetics of male fertility requires comprehensive genotype and phenotype data. Here, the authors characterize the transcriptional complexity of bovine male reproductive tissues to identify loci associated with male fertility.
- Xena Marie Mapel
- , Naveen Kumar Kadri
- & Hubert Pausch
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Article
| Open AccessSTYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation
The sperm flagellum is composed of tubulin-based microtubules and is critical for sperm motility and thus male fertility. Here, the authors show that STYXL1 regulates CCT complex-facilitated tubulin folding and is essential for sperm flagella formation.
- Yu Chen
- , Mengjiao Luo
- & Xuejiang Guo
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Article
| Open AccessPhase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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Article
| Open AccessSEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability
Pubertal timing in mammals depends on the function of GnRH neurons that innervate the median eminence (ME) of the hypothalamus. Here, the authors show that Semaphorin 6A regulates GnRH innervation and puberty onset by tuning vascular permeability at the ME.
- Antonella Lettieri
- , Roberto Oleari
- & Anna Cariboni
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Comment
| Open AccessTime for global health policy and research leaders to prioritize endometriosis
Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.
- Linda C. Giudice
- , Andrew W. Horne
- & Stacey A. Missmer
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Article
| Open AccessMaternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring
The authors show that maternal high-fat diet influences offspring’s ovarian reserve through maternal-embryonic cross-talk in mice and that maternal vitamin B1 supplementation could rescue ovarian primordial follicle reserve in mouse offspring.
- Wen-Xiang Liu
- , Hai-Ning Liu
- & Teng Zhang
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Article
| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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Article
| Open AccessA molecular staging model for accurately dating the endometrial biopsy
Natural variability in menstrual cycle length with rapid changes in gene expression makes it difficult to accurately compare different stages of the endometrial cycle. Here, the authors show a method for precisely determining endometrial cycle stage based on global gene expression that reveals remarkably synchronised daily changes for over 3,400 endometrial genes.
- W. T. Teh
- , J. Chung
- & P. A. W. Rogers
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Article
| Open AccessDecoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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Article
| Open AccessControl of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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Article
| Open AccessSYPL1 defines a vesicular pathway essential for sperm cytoplasmic droplet formation and male fertility
The cytoplasmic droplet is an elusive structure of mammalian sperm. Here, the authors uncover a key gene that defines a vesicular pathway essential for cytoplasmic droplet formation and male fertility.
- Jiali Liu
- , Louis Hermo
- & Chen Chen
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Article
| Open AccessMicrodiversity of the vaginal microbiome is associated with preterm birth
Here, Liao et al. analyze the vaginal microbiome during pregnancy, and find a unique population genetic structure associated with preterm birth, suggesting that evolutionary processes acting on vaginal bacteria may play a role in prematurity.
- Jingqiu Liao
- , Liat Shenhav
- & Tal Korem
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Article
| Open AccessThe role of mechano-regulated YAP/TAZ in erectile dysfunction
Phosphodiesterase type 5 inhibitors (PDE5is) are used to treat erectile dysfunction, however, not all patients respond to PDE5i treatment. Here the authors report that YAP/TAZ activity contributes to erectile dysfunction and targeting YAP/TAZ improves erectile function in a PDE5i non-respondent rat model.
- Mintao Ji
- , Dongsheng Chen
- & Lei Chang
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Article
| Open AccessCFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Progesterone (P4) signalling is involved in physiological control of the endometrium and contributes to the pathogenesis of endometrial diseases such as endometriosis. Here the authors report that CFP1, a regulator of histone methylation, controls endometrial responses to P4 and lack of endometrial CFP1 leads to failure of embryo implantation and exacerbated experimental endometriosis in mice.
- Seung Chel Yang
- , Mira Park
- & Haengseok Song
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Article
| Open AccessARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis
Male organisms produce huge numbers of sperm each day, with defects in the process resulting infertility. Here they show that arrestin domain-containing 5 (ARRDC5) is a testis-specific molecule required for mammalian spermatogenesis.
- Mariana I. Giassetti
- , Deqiang Miao
- & Jon M. Oatley
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Article
| Open AccessEvidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.
- Eeva Sliz
- , Jaakko S. Tyrmi
- & Johannes Kettunen
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Article
| Open AccessDiverse monogenic subforms of human spermatogenic failure
The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.
- Liina Nagirnaja
- , Alexandra M. Lopes
- & Donald F. Conrad
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Article
| Open AccessMicroencapsulation and nanowarming enables vitrification cryopreservation of mouse preantral follicles
Vitrification of preantral follicles is a promising strategy for female fertility preservation, but requires high concentrations of toxic cryoprotectants. Here, the authors accomplish follicle vitrification with low cryoprotectants by taking advantage of microencapsulation and nanowarming.
- Conghui Tian
- , Lingxiao Shen
- & Gang Zhao
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Article
| Open AccessDefinition of the estrogen negative feedback pathway controlling the GnRH pulse generator in female mice
Estrogen secreted by the ovary controls how the brain drives pulsatile reproductive hormone secretion. The authors show that in mice, estrogen receptor alpha within a specific population of hypothalamic kisspeptin neurons is the principal pathway through which estrogen brings about this classic negative feedback pathway common to all mammals.
- H. James McQuillan
- , Jenny Clarkson
- & Allan E. Herbison
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Article
| Open AccessTargeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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Article
| Open AccessBNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.
- Feixia Wang
- , Yifeng Liu
- & Dan Zhang
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Article
| Open AccessSingle-cell transcriptome atlas of the human corpus cavernosum
The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes physiological and psychological problems. Here the authors perform single-cell RNA-sequencing on corpus cavernosum samples from males with normal erection and erectile dysfunction patients, providing insights into this pathology.
- LiangYu Zhao
- , Sha Han
- & Zheng Li
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Article
| Open AccessNestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing
The regulatory mechanisms contributing to male reproductive ageing are unknown. Here, the authors show that Nestin-dependent mito-ER contacts (MERCs) regulate stem Leydig cell (SLC) senescence and provide insights into SLCs-targeting therapies.
- Senyu Yao
- , Xiaoyue Wei
- & Jiancheng Wang
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Article
| Open AccesshnRNPH1 recruits PTBP2 and SRSF3 to modulate alternative splicing in germ cells
Coordinated regulation of alternative splicing is essential for germ cell development. Here, the authors report that hnRNPH1 interacts with alternative splicing factors PTBP2 and SRSF3 in the germline to regulate pre-mRNA alternative splicing.
- Shenglei Feng
- , Jinmei Li
- & Shuiqiao Yuan
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Article
| Open AccessDynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging
Developmental potential of oocytes decreases in women of advanced age. Here the authors observe impaired meiosis-coupled mRNA decay and reduced CXXC1-maintained histone H3K4 trimethylation in old oocytes of mouse and humans.
- Yun-Wen Wu
- , Sen Li
- & Qian-Qian Sha
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Article
| Open AccessFunctional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation
Trophoblast stem cells can be derived from human blastocysts and first-trimester, but not term, cytotrophoblasts. Here the authors show that induction efficiency of cytotrophoblast is determined by antagonism between GCM1 and ΔNp63α and manipulating this antagonism facilitates derivation of TS cells from term placenta.
- Liang-Jie Wang
- , Chie-Pein Chen
- & Hungwen Chen
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Article
| Open AccessA microphysiological model of human trophoblast invasion during implantation
Normal and abnormal pregnancy is challenging to study and involves complex interactions between maternal and fetal cells. Here the authors present an implantation-on-a-chip device capable of modeling trophoblast invasion, a process critical to the establishment of pregnancy.
- Ju Young Park
- , Sneha Mani
- & Dan Dongeun Huh
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Article
| Open AccessLoss of MIG-6 results in endometrial progesterone resistance via ERBB2
Female subfertility is highly associated with endometriosis. Here the authors show that progesterone-induced MIG-6 is reduced in endometrium of infertile women and non-human primates with endometriosis, and in a mouse model find that Erbb2 is the key mediator of Mig-6 loss induced endometriosis-related infertility.
- Jung-Yoon Yoo
- , Tae Hoon Kim
- & Jae-Wook Jeong
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Article
| Open AccessMenin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling
The decidualization of endometrial stroma is critical for pregnancy maintenance. Here the authors reveal that Menin ensures the expression of PTX3 through H3K4me3 modification, to balance the BMP and FGF signal in the decidua for normal pregnancy.
- Mengying Liu
- , Wenbo Deng
- & Shuangbo Kong
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Article
| Open AccessTrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice
Qin et al. report that an agonistic antibody targeting the BDNF receptor TrkB promotes follicle development and oocyte maturation, and reverse ovarian deficits and infertility in aged and cyclophosphamide-induced premature ovarian failure model mice.
- Xunsi Qin
- , Yue Zhao
- & Bai Lu
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Article
| Open AccessA de novo paradigm for male infertility
Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.
- M. S. Oud
- , R. M. Smits
- & J. A. Veltman
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Article
| Open AccessCell-fate transition and determination analysis of mouse male germ cells throughout development
The full-term developmental profile of male germ cells remains undefined. Here, the authors use single-cell sequencing to investigate the transcriptome landscapes of mouse male germ cells throughout development and find several critical regulators for prenatal cell-fate determination.
- Jiexiang Zhao
- , Ping Lu
- & Xiao-Yang Zhao
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Article
| Open AccessAging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia
Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here the authors perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia.
- Massimo Alfano
- , Anna Sofia Tascini
- & Andrea Salonia
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Article
| Open AccessThe missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus
The sperm head-to-tail coupling apparatus ensures sperm head-tail integrity, but mechanistic insights remain limited. Here the authors demonstrate that CENTLEIN links and controls the interaction between SUN5 and PMFBP1, indicating that its impairments might be associated with acephalic spermatozoa syndrome.
- Ying Zhang
- , Chao Liu
- & Li Yuan
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Article
| Open AccessCirculating trophoblast cell clusters for early detection of placenta accreta spectrum disorders
Placenta accreta spectrum (PAS) is a high-risk obstetrical complication associated with significant morbidity and mortality. Here the authors discover a uniquely high prevalence of circulating trophoblasts clusters in PAS and explore their diagnostic potential to augment current diagnostic modalities for the early detection of PAS.
- Yalda Afshar
- , Jiantong Dong
- & Yazhen Zhu
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Article
| Open AccessLow chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk
Abnormal placentation is associated with recurrent spontaneous abortion (RSA) risk. Here the authors report that low embryonic villous succinate level associates with risk of RSA in patients, and increasing succinate levels is sufficient to reduce the incidence rate in a mouse model of spontaneous abortion.
- Xiao-Hui Wang
- , Sha Xu
- & Jian-Yuan Zhao
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Article
| Open AccessOpen fire exposure increases the risk of pregnancy loss in South Asia
Open fires can increase heavy exposure to hazardous particulate matters, and thus harm human health, particularly among the vulnerable individuals, such as pregnant women. Here, the authors show an association between maternal exposure to fire smoke and increased risk of pregnancy loss in South Asia.
- Tao Xue
- , Guannan Geng
- & Tong Zhu
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Article
| Open AccessThe RNA landscape of the human placenta in health and disease
Placental dysfunction can have catastrophic or barely discernible effects ranging from miscarriage to apparently normal birth. Here the authors present a comprehensive analysis of the human placental transcriptome and identify circular RNAs and piRNAs.
- Sungsam Gong
- , Francesca Gaccioli
- & D. Stephen Charnock-Jones
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Article
| Open AccessSingle-cell transcriptome profiling of the vaginal wall in women with severe anterior vaginal prolapse
Anterior vaginal prolapse (AVP), the most common form of pelvic organ prolapse, has deleterious effects on women’s health. Here the authors employ single-cell RNA-seq to construct a transcriptomic atlas of vaginal wall cells from AVP patients, and find that extracellular matrix dysregulation and immune reaction are associated with AVP.
- Yaqian Li
- , Qing-Yang Zhang
- & Lan Zhu
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Article
| Open AccessThe genetic architecture of sporadic and multiple consecutive miscarriage
Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.
- Triin Laisk
- , Ana Luiza G. Soares
- & Cecilia M. Lindgren
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Article
| Open AccessGenetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
- Valgerdur Steinthorsdottir
- , Ralph McGinnis
- & Linda Morgan
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Article
| Open AccessSingle-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells
Non-obstructive azoospermia affects 1% of men. Here, authors perform single-cell transcriptomic analysis of human testicular cells from healthy donors and non-obstructive azoospermia patients and find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from patients.
- LiangYu Zhao
- , ChenCheng Yao
- & Zheng Li
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Article
| Open AccessDefining the impact of dietary macronutrient balance on PCOS traits
Lifestyle interventions are first-line treatment for women with polycystic ovary syndrome (PCOS), but the optimal diet remains undefined. Here the authors identify an optimum dietary macronutrient balance that can rectify PCOS reproductive traits in a mouse model of PCOS, while metabolic features were less sensitive to diet changes.
- Valentina Rodriguez Paris
- , Samantha M. Solon-Biet
- & Kirsty A. Walters
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Article
| Open AccessDynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans
How maternal RNA clearance is regulated in human preimplantation embryos is unclear. Here, the authors show there is a potential correlation between maternal mRNA decay defects and early developmental arrest from in vitro fertilized human embryos, suggesting that M-decay and Z-decay pathways may regulate such early development.
- Qian-Qian Sha
- , Wei Zheng
- & Heng-Yu Fan
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Article
| Open AccessAccounting for diverse evolutionary forces reveals mosaic patterns of selection on human preterm birth loci
There is a need for analytical frameworks to investigate the evolution of complex genetic traits. Here, the authors develop an approach to simultaneously evaluate different evolutionary signatures on trait-associated genetic variants for complex traits and apply it to study spontaneous preterm birth.
- Abigail L. LaBella
- , Abin Abraham
- & John A. Capra
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Article
| Open AccessFunctional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells
Injury of corpus cavernosa results in erectile dysfunction, and repair leading to restoration of function is difficult. Here the authors construct 3D printed hydrogel constructs seeded with HIF-1α-expressing muscle derived stem cells to restore corpus function in a rabbit model.
- Geng An
- , Feixiang Guo
- & Chuanbin Mao
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Article
| Open AccessDysregulation of bile acids increases the risk for preterm birth in pregnant women
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications with limited treatment options. Here the authors show that dysregulation of bile acids increases risk for PTB in pregnant women while restoring bile acid homeostasis delays or prevents PTB in the mouse models.
- Sangmin You
- , Ai-Min Cui
- & Ruitang Deng
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Article
| Open AccessAltered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas
Somatic mutations in MED12 have been implicated as the causal genetic lesion in the majority of uterine leiomyomas. Here, the authors profile the chromatin landscape of matched normal and leiomyoma tissues and find that changes in enhancer acetylation, enhancer-promoter interaction strength, differential enhancer usage and transcription factor AP-1 occupancy are significant drivers of transcriptional dysregulation in MED12 mutant leiomyomas.
- Mthabisi B. Moyo
- , J. Brandon Parker
- & Debabrata Chakravarti