Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA648914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12330744.fastq.gz | Fastqsanger.gz | |||
| SRR12330745.fastq.gz | Fastqsanger.gz | |||
| SRR12330746.fastq.gz | Fastqsanger.gz | |||
| SRR12330747.fastq.gz | Fastqsanger.gz | |||
| SRR12330748.fastq.gz | Fastqsanger.gz |
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Project description:The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth. Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian (‘Placental') mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling, an innovation of Eutherians, thereby allowing blastocyst implantation. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts. Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data connect HAND2 expression at the maternal-fetal interface with the evolution of implantation and gestation length regulation, and preterm birth.
2020-08-26 | GSE155322 | GEO
Project description:The developmental origins and evolutionary histories of cell types, tissues and organ systems contribute to the ways in which their dysfunction leads to disease. In mammals for example, the nature and extent of maternal-fetal interactions, how those interactions develop, and their evolutionary history likely influence diseases of pregnancy such as infertility and preterm birth. Here we show genes that evolved to be expressed at the maternal-fetal interface in Eutherian (‘Placental') mammals play essential roles in the evolution of pregnancy and are associated with immune system disorders and preterm birth. Among these genes is the transcription factor HAND2, which suppresses estrogen signaling, an innovation of Eutherians, thereby allowing blastocyst implantation. We found that HAND2 is dynamically expressed in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to reach a low at term. HAND2 regulates a small but distinct set of target genes in endometrial stromal fibroblasts including the cytokine IL15, which was also dynamically expressed throughout the menstrual cycle and gestation, and promoted the migration of natural killer cells and extravillous cytotrophoblasts. Remarkably, we found that the HAND2 promoter loops to a distal enhancer containing SNPs implicated in the regulation of gestation length and birth weight. Collectively, these data connect HAND2 expression at the maternal-fetal interface with the evolution of implantation and gestation length regulation, and preterm birth.
2020-07-28 | GSE155170 | GEO
Project description:Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length
| PRJNA649314 | ENA
Project description:The developmental origins and evolutionary histories of cell types, tissues, and organs contribute to the ways in which their dysfunction produces disease. In mammals, the nature, development and evolution of maternal-fetal interactions likely influence diseases of pregnancy. Here we show genes that evolved expression at the maternal-fetal interface in Eutherian mammals play essential roles in the evolution of pregnancy and are associated with immunological disorders and preterm birth. Among these genes is HAND2, a transcription factor that suppresses estrogen signaling, a Eutherian innovation allowing blastocyst implantation. We found dynamic HAND2 expression in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to a low at term. HAND2 regulates a distinct set of genes in endometrial stromal fibroblasts including IL15, a cytokine also exhibiting dynamic expression throughout the menstrual cycle and gestation, promoting migration of natural killer cells and extravillous cytotrophoblasts. We demonstrate that HAND2 promoter loops to an enhancer containing SNPs implicated in birth weight and gestation length regulation. Collectively, these data connect HAND2 expression at the maternal-fetal interface with evolution of implantation and gestational regulation, and preterm birth.
| S-EPMC7943190 | biostudies-literature
Project description:Our previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity. To identify the downstream targets of Hand2 in the uterus, we performed gene expression profling of uterine stromal cells isolated from Hand2-null mice and the corresponding controls on day4 of pregnancy (the time of implantation). The microarray results revealed elevated expression of mRNAs corresponding to several members of the fibroblast growth factor family in uterine stroma of Hand2-ablated mice. These factors act as paracrine mediators of mitogenic effects of estrogen on the epithleium. Thus, Hand2 is a critical regulator of the uteirne stromal-epithelial communication that directs proper steroid regulation conducive for establshment of pregnancy. We performed conditional ablation of Hand2 in the mouse uterus using the PRcre mouse model. As Hand2 expression is restricted to stromal comaprtment, we isolated uterine stromal cells from day4 pregnant mice (n=5 for each genotype), purified total RNA from these cells, pooled these samples and then hybridized to high density affymetrix microarrays. Control vs. KO.
2011-06-03 | E-GEOD-25881 | biostudies-arrayexpress
Project description:Our previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity. To identify the downstream targets of Hand2 in the uterus, we performed gene expression profling of uterine stromal cells isolated from Hand2-null mice and the corresponding controls on day4 of pregnancy (the time of implantation). The microarray results revealed elevated expression of mRNAs corresponding to several members of the fibroblast growth factor family in uterine stroma of Hand2-ablated mice. These factors act as paracrine mediators of mitogenic effects of estrogen on the epithleium. Thus, Hand2 is a critical regulator of the uteirne stromal-epithelial communication that directs proper steroid regulation conducive for establshment of pregnancy.
2011-06-03 | GSE25881 | GEO
Project description:Timing mechanisms in biology remain poorly understood. As one prime example, little is known about the mechanisms that specify how long the gestating uterus will remain quiescent before entering labor1. Our lack of insight into this fundamental question, which applies to all mammalian species, also limits investigation into potential causes of preterm labor, a major human pregnancy complication. Here, we provide evidence that gestation length in mice is determined by an epigenetic timer that runs autonomously within the fibroblasts of the pregnant uterus. The timer is set during the peri-implantation period when select genomic loci establish appropriate levels of the repressive histone mark H3K27me3. These loci then progressively lose H3K27me3, thereby scheduling the uterine cell state transitions and associated gene expression changes of late gestation that are the proximal mediators of labor onset. Overwinding of the timer’s peri-implantation setpoint via genetic ablation of the histone demethylase KDM6B delays these transitions and extends gestation length. These results provide insight into how complex tissues employ epigenetic pathways to specify the timing of discrete biological events. We also anticipate that further dissection of the ways such uterine programming controls gestation length may suggest novel approaches for improving human pregnancy outcomes.
2024-12-20 | GSE242864 | GEO
Project description:HAND2 regulates regional chromation modification [HAND2-knockdown_histone_ChIPseq]
| PRJNA762918 | ENA
Project description:Acquisition of the lower jaw (mandible) was evolutionarily important for jawed vertebrates. In humans, syndromic craniofacial malformations often accompany jaw anomalies. Hand2 is involved in coordinating the developmental network of mandibles and the oral apparatus through Hand2-downstream genes and is therefore a major determinant of jaw identity. We used microarrays to detail the global programme of gene expression involved in mandible specification and identified distinct classes of up-regulated genes during this process. Wild-type and Hand2 mutant (Hand2 CAT/+; Wnt1-Cre) embryos were collected at Embryonic day (E) 11.5 or E12.5 for RNA extraction and hybridization on Affymetrix microarrays.
2015-12-15 | E-GEOD-75805 | biostudies-arrayexpress
Project description:Early gestational loss occurs in ~20% of all clinically recognized human pregnancies and is a significant cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. The SWI/SNF remodeling complex containing PBRM1and BRG1 is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although pre-implantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathway and uterine receptivity. Hand2 is a bHLH transcription factor required for embryo implantation. We report a new enhancer of Hand2 in stromal cells that requires PBRM1 for epigenetic histone modifications and coactivator recruitment. In Pbrm1cKO mice, perturbations at the enhancer site compromised Hand2 transcription, disrupts the fibroblast growth factor signaling pathway and prevents normal Stromal- Epithelial crosstalk and embryo implantation. The resultant mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.
2024-01-14 | GSE229368 | GEO