Embryonic Environment Research Articles

Systemic interindividual DNA methylation variants in cattle share major hallmarks with those in humans

BackgroundWe recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle.ResultsFocusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, our approach identifies 217 cattle CoRSIVs, a subset of which we independently validate by bisulfite pyrosequencing. Similar to human CoRSIVs, those in cattle are strongly associated with genetic variation. Also as in humans, we show that establishment of DNA methylation at cattle CoRSIVs is particularly sensitive to early embryonic environment, in the context of embryo culture during assisted reproduction.ConclusionsOur data indicate that CoRSIVs exist in cattle, as in humans, suggesting these systemic epigenetic variants may be common to mammals in general. To the extent that individual epigenetic variation at cattle CoRSIVs affects phenotypic outcomes, assessment of CoRSIV methylation at birth may become an important tool for optimizing agriculturally important traits. Moreover, adjusting embryo culture conditions during assisted reproduction may provide opportunities to tailor agricultural outcomes by engineering CoRSIV methylation profiles.

Chloride Modulates Central pH Sensitivity and Plasticity of Brainstem Breathing-Related Biorhythms in Zebra Finch Embryos.

All terrestrial vertebrate life must transition from aquatic gas exchange in the embryonic environment to aerial or pulmonary respiration at birth. In addition to being able to breathe air, neonates must possess functional sensory feedback systems for maintaining acid-base balance. Respiratory neurons in the brainstem act as pH sensors that can adjust breathing to regulate systemic pH. The central pH sensitivity of breathing-related motor output develops over the embryonic period in the zebra finch (Taeniopygia guttata). Due to the key role of chloride ions in electrochemical stability and developmental plasticity, we tested chloride's role in the development of central pH sensitivity. We blocked gamma-aminobutyric acid-A receptors and cation-chloride cotransport that subtly modulated the low-pH effects on early breathing biorhythms. Further, chloride-free artificial cerebrospinal fluid altered the pattern and timing of breathing biorhythms and blocked the stimulating effect of acidosis in E12-14 brainstems. Early and middle stage embryos exhibited rebound plasticity in brainstem motor outputs during low-pH treatment, which was eliminated by chloride-free solution. Results show that chloride modulates low-pH sensitivity and rebound plasticity in the zebra finch embryonic brainstem, but work is needed to determine the cellular and circuit mechanisms that control functional chloride balance during acid-base disturbances.

Hatching plasticity is associated with a more advanced stage at hatching in an Ambystoma with terrestrial eggs.

Hatching plasticity allows animals to initiate hatching in response to environmental cues including predation, flooding, and hypoxia. In species with terrestrial eggs but aquatic larvae, hatching plasticity often manifests as extended development of embryos when water is not available. Although these effects are taxonomically widespread, little attention has focused on differences in plasticity across closely related species with terrestrial and aquatic embryos. We propose that the terrestrial embryonic environment favors slower and prolonged development and, consequently, that we should see differences in development between closely related species that differ in where they lay their eggs. We test this hypothesis by comparing embryonic development between two mole salamanders, Ambystoma opacum and A. annulatum. Most Ambystoma lay eggs submerged in ponds but A. opacum lays its eggs on land, where hatching is triggered when eggs are submerged by rising pond levels. Embryos of both species were reared under common laboratory conditions simulating both aquatic and terrestrial nest sites. Consistent with our hypothesis, we found that A. opacum embryos exhibited slower development and took longer to hatch than A. annulatum embryos in both rearing environments. Furthermore, we observed in A. opacum a plasticity in hatching stage that was absent in A. annulatum. Our results indicate that the terrestrial-laying A. opacum has evolved slower and prolonged development relative to its aquatic-laying congener and suggest that embryonic survival in the unpredictable terrestrial environment may be facilitated by developmental plasticity.

Modeling Fetal Alcohol Spectrum Disorders in Zebrafish to Characterize the Impact of an Adverse Embryonic Environment on Adult Social Behavior.

Fetal alcohol spectrum disorders (FASD) describe all alcohol-induced birth defects. Birth defects such as growth deficiencies, craniofacial, behavioral, and cognitive abnormalities are associated with FASD. Social difficulties are common behavioral abnormalities associated with FASD and often result in serious health issues. Animal models are critical to understanding the mechanisms responsible for ethanol-induced social defects. Zebrafish are social vertebrates that produce externally fertilized transparent eggs; these characteristics provide researchers with a precise yet simple procedure for creating the FASD phenotype and an innate behavior that can be leveraged to model the social deficits associated with FASD. Thus, zebrafish are ideal for characterizing the social deficits of FASD. The goal of the current protocol is to provide the user with a simple behavioral assay that can be used to characterize the consequences of a negative environment early during development and the effects it can have on social behavior in adulthood. The protocol can be used to characterize the effect mutations or teratogens have on adult social behavior. The protocol outlined here demonstrates how to characterize the social behavior of individual fish during a 20-min social assay. Furthermore, the data obtained using the current protocol provides evidence that the protocol can be used to characterize the effects of embryonic ethanol-induced social defects in adult zebrafish.

The embryonic thermal environment has positive but weak effects on thermal tolerance later in life in the aquatic invertebrate Gammarus chevreuxi

Recent evidence suggests that the adult phenotype is influenced by temperatures experienced in early life. However, our understanding of the extent to which the embryonic environment can modulate thermal tolerance later in life is limited, owing to the paucity of studies with appropriate experimental designs to test for this form of developmental plasticity. We investigated whether the thermal environment experienced during embryonic development affects thermal limits in later life. Embryos of the estuarine amphipod Gammarus chevreuxi were incubated until hatching to 15 °C, 20 °C and 25 °C, then reared under a common temperature. Using thermal ramping assays, we determined upper thermal limits in juveniles, four weeks post-hatch. Individuals exposed to higher temperatures during embryonic development displayed greater thermal tolerance as juveniles (acclimation response ratio ≈ 0.10–0.25 for upper lethal temperature). However, we suggest that the degree of developmental plasticity observed is limited, and will provide little benefit under future climate change scenarios.

Embryonic manipulations shape life-long, heritable stress responses through complex epigenetic mechanisms: a review.

Enhancing an organism's likelihood of survival hinges on fostering a balanced and adaptable development of robust stress response systems. This critical process is significantly influenced by the embryonic environment, which plays a pivotal role in shaping neural circuits that define the stress response set-point. While certain embryonic conditions offer advantageous outcomes, others can lead to maladaptive responses. The establishment of this response set-point during embryonic development can exert life-long and inheritable effects on an organism's physiology and behavior. This review highlights the significance of multilevel epigenetic regulation and the intricate cross-talk among these layers in response to heat stress during the embryonic period, with a particular focus on insights gained from the avian model.

Tithonian mafic intrusions in north-central Newfoundland: link to Atlantic rifting?

The small volume, Mesozoic alkali gabbro intrusions of the Budgell Harbour and Dildo Pond stocks and associated alkaline lamprophyre dykes in Notre Dame Bay in Newfoundland are an example of onshore magmatism that may be associated with North Atlantic Ocean opening. Chemical abrasion isotope dilution thermal ionization mass spectrometry U–Pb dating of zircon from Budgell Harbour Stock drill core samples yielded a weighted average 206Pb/238U age of 147.9 ± 0.5 Ma (95% confidence interval, mean square weighted deviation = 0.10). Five 40Ar/39Ar laser step-heating, single phlogopite grain analyses from the Budgell Harbour and Dildo Pond stocks, plus a lamprophyre dyke, yielded ages ranging from 146.3 ± 0.2 to 149.5 ± 0.5 Ma. The data demonstrate a ca. 148 Ma (Jurassic and Tithonian) alkaline magmatic event in Newfoundland, contemporaneous with rifting and offshore basin formation. These new age data and published determinations from magmatic rocks on conjugate margins and adjacent regions reveal long-lived episodic magmatism in the embryonic North Atlantic rift environment. We propose a new model whereby magmatism occurred in Notre Dame Bay at the convergence of older crustal-scale faults and localized Moho depth variations that may have triggered lithospheric mantle melting through isothermal, distal, and edge-driven upwelling related to regional extension.

Gastruloid-derived primordial germ cell-like cells develop dynamically within integrated tissues.

Primordial germ cells (PGCs) are the early embryonic precursors of gametes - sperm and egg cells. PGC-like cells (PGCLCs) can currently be derived in vitro from pluripotent cells exposed to signalling cocktails and aggregated into large embryonic bodies, but these do not recapitulate the native embryonic environment during PGC formation. Here, we show that mouse gastruloids, a three-dimensional in vitro model of gastrulation, contain a population of gastruloid-derived PGCLCs (Gld-PGCLCs) that resemble early PGCs in vivo. Importantly, the conserved organisation of mouse gastruloids leads to coordinated spatial and temporal localisation of Gld-PGCLCs relative to surrounding somatic cells, even in the absence of specific exogenous PGC-specific signalling or extra-embryonic tissues. In gastruloids, self-organised interactions between cells and tissues, including the endodermal epithelium, enables the specification and subsequent maturation of a pool of Gld-PGCLCs. As such, mouse gastruloids represent a new source of PGCLCs in vitro and, owing to their inherent co-development, serve as a novel model to study the dynamics of PGC development within integrated tissue environments.

Ectopic Lipid Accumulation Correlates with Cellular Stress in Rabbit Blastocysts from Diabetic Mothers.

Maternal diabetes mellitus in early pregnancy leads to hyperlipidemia in reproductive tract organs and an altered embryonic environment. To investigate the consequences on embryonic metabolism, the effect of high environmental-lipid levels was studied in rabbit blastocysts cultured with a lipid mixture in vitro and in blastocysts from diabetic, hyperlipidemic rabbits in vivo. The gene and protein expression of marker molecules involved in lipid metabolism and stress response were analyzed. In diabetic rabbits, the expression of embryoblast genes encoding carnitine palmityl transferase 1 and peroxisome proliferator-activated receptors α and γ increased, whereas trophoblast genes encoding for proteins associated with fatty acid synthesis and β-oxidation decreased. Markers for endoplasmic (activating transcription factor 4) and oxidative stress (nuclear factor erythroid 2-related factor 2) were increased in embryoblasts, while markers for cellular redox status (superoxide dismutase 2) and stress (heat shock protein 70) were increased in trophoblasts from diabetic rabbits. The observed regulation pattern in vivo was consistent with an adaptation response to the hyperlipidemic environment, suggesting that maternal lipids have an impact on the intracellular metabolism of the preimplantation embryo in diabetic pregnancy and that embryoblasts are particularly vulnerable to metabolic stress.

289-LB: Intestinal Stem Cells as a Source of Insulin-Positive Beta-Like Cells for Treating Diabetes

Shortage of functional pancreatic beta-cells is the basic cause of type 1 and some late-stage type 2 diabetes, making generation of new beta-cells from stem cells a promising strategy for treating diabetes. Intestinal stem cells (ISCs) are adult stem cells found in the base of the crypts of the adult intestine, which is responsible for the continuous life-long renewal of intestinal epithelia cells and thus could also be used a potential source for autologous transplantation. Unlike the most extensively studied bone marrow derived stem cells, ISCs share the advantage of having a common endodermic origin with beta-cells, making their differentiation into beta-cells easier. However, purifying ISCs has been a challenge. Here, we reported a novel method that successfully purifies ISCs from wildtype mice by exploiting their specific binding to a lectin. The only other cell type in the intestine that also binds to this lectin was found to be Paneth cells, which could be excluded through a negative selection for CD24. The purified Lectin+CD24-ISCs, confirmed by gene profiling, were labeled with a fluorescent tag and shown to differentiate into insulin-producing beta-like cells when injected into day 11.5 mouse embryonic pancreatic explants and grown for a week. Further analysis of gene profile alterations and signaling pathways allowed us to develop a time-sensitive protocol with recombinant growth factors to optimize the differentiation of ISCs into beta-like cells in vitro, without the need for an embryonic environment. Our results not only demonstrate a new method for purifying ISCs, but also their potential to differentiate into insulin-producing beta-like cells. This study provides a promising strategy for beta-cell replacement therapy in diabetes. Disclosure Y. Xiao: None. Y. Xiao: None. Y. Jiang: None. Funding University of Pittsburgh; Children?s Hospital of Pittsburgh; Cochrane-Weber Endowed Fund in Diabetes Research

Variation in Embryonic Metabolic Reaction Norms and the Role of the Environment.

AbstractEarly developmental environments can shape how organisms respond to later environments, but despite the potential for this phenomenon to alter the evolution of phenotypes and their underlying mechanisms in variable environments, details of this process are not understood. For example, both temperature and parental age can alter offspring metabolic plasticity and growth within species, yet the extent of such effects is unknown. We measured the reaction norms of embryonic heart rate in response to egg temperature and the change in egg mass over the incubation period in wild house sparrows. Using Bayesian linear mixed models, we estimated covariation in the intercepts and slopes of these reaction norms among clutches and eggs. We found that heart rate intercepts, not slopes, varied among clutches and that neither intercepts nor slopes varied among eggs within clutches. In contrast, egg mass intercepts and slopes varied among clutches and eggs. Ambient temperature did not explain variance in reaction norms. Instead, individuals from older mothers were more metabolically sensitive to egg temperature and lost less mass over the incubation period than individuals from younger mothers. Nevertheless, heart rate reaction norms and egg mass reaction norms did not covary. Our results suggest that early environments influenced by parents may contribute to variation in embryonic reaction norms. The structure of variation in embryonic reaction norms that exists both among clutches and among eggs demonstrates a complexity in plastic phenotypes that should be explored in future work. Furthermore, the potential for the embryonic environment to shape the reaction norms of other traits has implications for the evolution of plasticity more broadly.

The ups and downs of Pax6 in neural stem cells

Neural stem cells (NSCs) must rapidly adapt their transcriptional activity to the ever-changing embryonic environment. Currently, we have a limited understanding of how key transcription factors such as Pax6 are modulated at the protein level. In a recent issue of the JBC, Dong et al identifed a novel post-translational regulatory mechanism in which Kat2a-mediated lysine acetylation on Pax6 leads to its ubiquitination and ultimately its degradation via the proteasome pathway, thereby determining whether NSCs undergo proliferation or neuronal differentiation.

Hyperglycemia affects neuronal differentiation and Nestin, FOXO1, and LMO3 mRNA expression of human Wharton's jelly mesenchymal stem cells of children from diabetic mothers

Pregestational Diabetes Mellitus (PDM) during pregnancy constitutes an unfavorable embryonic and fetal development environment, with a high incidence of congenital malformations (CM). Neural tube defects are the second most common type of CM in children of diabetic mothers (CDM), who also have an elevated risk of developing neurodevelopmental disorders. The mechanisms that lead to these neuronal disorders in CDM are not yet fully understood. The present study aimed to know the effect of hyperglycemia on proliferation, neuronal differentiation percentage, and expression of neuronal differentiation mRNA markers in human umbilical cord Wharton's jelly mesenchymal stem cells (hUCWJMSC) of children from normoglycemic pregnancies (NGP) and PDM. We isolated and characterized hUCWJMSC by flow cytometry, immunofluorescence, RT-PCR and were induced to differentiate into adipocytes, osteocytes, and neurons. Proliferation assays were performed to determine the doubling time, and Nestin, TUBB3, FOXO1, KCNK2, LMO3, and MAP2 mRNA gene expression was assessed by semiquantitative RT-PCR. Hyperglycemia significantly decreased proliferation and neuronal differentiation percentage in NGP and PDM cells treated with 40 mM d-glucose. Nestin mRNA expression decreased under control glycemic conditions, while FOXO1, KCNK2, LMO3, and MAP2 mRNA expression increased during neuronal differentiation in both NGP and PDM cells. On the other hand, under hyperglycemic conditions, Nestin was significantly decreased in cells from NGP but not in cells from PDM, while mRNA expression of FOXO1 and LMO3 was significantly increased in cells from NGP, but not in cells from PDM. We found evidence that maternal PDM, with hyperglycemia in culture, affects the biological properties of fetal cells. All these results could be part of fetal programming.

Extracellular Vesicles and Membrane Protrusions in Developmental Signaling.

During embryonic development, cells communicate with each other to determine cell fate, guide migration, and shape morphogenesis. While the relevant secreted factors and their downstream target genes have been characterized extensively, how these signals travel between embryonic cells is still emerging. Evidence is accumulating that extracellular vesicles (EVs), which are well defined in cell culture and cancer, offer a crucial means of communication in embryos. Moreover, the release and/or reception of EVs is often facilitated by fine cellular protrusions, which have a history of study in development. However, due in part to the complexities of identifying fragile nanometer-scale extracellular structures within the three-dimensional embryonic environment, the nomenclature of developmental EVs and protrusions can be ambiguous, confounding progress. In this review, we provide a robust guide to categorizing these structures in order to enable comparisons between developmental systems and stages. Then, we discuss existing evidence supporting a role for EVs and fine cellular protrusions throughout development.

A detailed redescription of the mesoderm/neural crest cell boundary in the murine orbitotemporal region integrates the mammalian cranium into a pan-amniote cranial configuration.

The morphology of the mammalian chondrocranium appears to differ significantly from those of other amniotes, since the former possesses uniquely developed brain and cranial sensory organs. In particular, a question has long remained unanswered as to the developmental and evolutionary origins of a cartilaginous nodule called the ala hypochiasmatica. In this study, we investigated the embryonic origin of skeletal elements in the murine orbitotemporal region by combining genetic cell lineage analysis with detailed morphological observation. Our results showed that the mesodermal embryonic environment including the ala hypochiasmatica, which appeared as an isolated mesodermal distribution in the neural crest-derived prechordal region, is formed as a part of the mesoderm that continued from the chordal region during early chondrocranial development. The mesoderm/neural crest cell boundary in the head mesenchyme is modified through development, resulting in the secondary mesodermal expansion to invade into the prechordal region. We thus revealed that the ala hypochiasmatica develops as the frontier of the mesodermal sheet stretched along the cephalic flexure. These results suggest that the mammalian ala hypochiasmatica has evolved from a part of the mesodermal primary cranial wall in ancestral amniotes. In addition, the endoskeletal elements in the orbitotemporal region, such as the orbital cartilage, suprapterygoid articulation of the palatoquadrate, and trabecula, some of which were once believed to represent primitive traits of amniotes and to be lost in the mammalian lineage, have been confirmed to exist in the mammalian cranium. Consequently, the mammalian chondrocranium can now be explained in relation to the pan-amniote cranial configuration.

Does Embryonic Culture Environment Affect Ploidy Rates in ART Cycles: A Single Center Study in UK.

The purpose of the current study was to assess whether embryonic culture conditions has an impact on embryo ploidy in a preimplantation genetic testing for aneuploidy (PGT-A) cycle. In this retrospective single center cohort study, a total of 1099 blastocysts from 278 PGT-A cycles were analyzed. The generated blastocysts were biopsied on days 5 and 6. Inseminated oocytes were allocated in different incubators (benchtop and time lapse) and assisted zona hatching was performed on day 3 of embryo development to facilitate the biopsy process which was performed on days 5 and 6 (blastocyst stage). The average age across the groups was 38.7±3.6 years and the total number of mature eggs was 2912 which were randomly distributed across both incubators. The euploidy rate obtained from both groups showed a higher proportion of euploid embryos in the TLM incubator (37.03%, 95% CI 31.9-42.1) compared to those cultured in the BT incubator (30.4%, 95% CI 23.1-37.7). Regression analysis showed that female age remains to be the key variable driving euploidy rates (0.85, 95% CI 0.82-0.88) although incubator type could be an important covariable (0.54, 95% CI 0.45-0.59). A subgroup analysis of 74 single euploid embryo transfers showed comparable pregnancy and live birth rates. This large cohort study demonstrates that uninterrupted controlled culture environment provides increased probability to develop euploid embryo in a PGT-A cycle. However, further evaluation is required to assess how environmental culture conditions at a cellular level could affect epigenetic mechanisms in embryo development and higher aneuploidy rate.

The Effects of Ovalbumin on Proliferation, Migration, and Stemness Properties of Chemoresistant SW480 Colon Cancer Cells

Egg peptides are factors in the embryonic environment with many significant biological activities, such as anticancer activity. Therefore, the current study investigates the effect of egg ovalbumin (OVA) on survival, cell cycle, self-renewal ability, stemness properties, and migration in SW480 colon cancer cells and 5-fluorouracil (5FU) resistant subgroup. MTT test was performed to assess cell viability. Flow cytometry was employed to analyze the cell cycle. Clonogenic assay and spheroid formation were used to assess the effect of OVA on self-renewal and stemness properties. Wound healing assay and RT-PCR were performed to analyze migration and gene mRNA expression. We demonstrated that OVA (8 and 12 mg/ml) attenuated cell viability, induced cell-cycle arrest, inhibited colony formation, and non-significantly reduced spheroid formation and migration in both cell lines. Furthermore, OVA downregulated the expression of Nanog, c-Myc, and NDRG1 in both cells, suggesting a stemness and self-renewal attenuation by OVA. In conclusion, OVA exposure inhibited the 5FU-SW480 chemo-resistant subpopulation growth by inducing cell cycle arrest and diminishing self-renewal and partially stemness properties of colon cancer cells.

Cross-tissue and generation predictability of relative Wolbachia densities in the mosquito Aedes aegypti

BackgroundThe insect endosymbiotic bacterium Wolbachia is being deployed in field populations of the mosquito Aedes aegypti for biological control. This microbe prevents the replication of human disease-causing viruses inside the vector, including dengue, Zika and chikungunya. Relative Wolbachia densities may in part predict the strength of this ‘viral blocking’ effect. Additionally, Wolbachia densities may affect the strength of the reproductive manipulations it induces, including cytoplasmic incompatibility (CI), maternal inheritance rates or induced fitness effects in the insect host. High rates of CI and maternal inheritance and low rates of fitness effects are also key to the successful spreading of Wolbachia through vector populations and its successful use in biocontrol. The factors that control Wolbachia densities are not completely understood.MethodsWe used quantitative PCR-based methods to estimate relative density of the Wolbachia wAlbB strain in both the somatic and reproductive tissues of adult male and female mosquitoes, as well as in eggs. Using correlation analyses, we assessed whether densities in one tissue predict those in others within the same individual, but also across generations.ResultsWe found little relationship among the relative Wolbachia densities of different tissues in the same host. The results also show that there was very little relationship between Wolbachia densities in parents and those in offspring, both in the same and different tissues. The one exception was with ovary–egg relationships, where there was a strong positive association. Relative Wolbachia densities in reproductive tissues were always greater than those in the somatic tissues. Additionally, the densities were consistent in females over their lifetime regardless of tissue, whereas they were generally higher and more variable in males, particularly in the testes.ConclusionsOur results indicate that either stochastic processes or local tissue-based physiologies are more likely factors dictating Wolbachia densities in Ae. aegypti individuals, rather than shared embryonic environments or heritable genetic effects of the mosquito genome. These findings have implications for understanding how relative Wolbachia densities may evolve and/or be maintained over the long term in Ae. aegypti.Graphical

CellComm infers cellular crosstalk that drives haematopoietic stem and progenitor cell development.

Intercellular communication orchestrates a multitude of physiologic and pathologic conditions. Algorithms to infer cell-cell communication and predict downstream signalling and regulatory networks are needed to illuminate mechanisms of stem cell differentiation and tissue development. Here, to fill this gap, we developed and applied CellComm to investigate how the aorta-gonad-mesonephros microenvironment dictates haematopoietic stem and progenitor cell emergence. We identified key microenvironmental signals and transcriptional networks that regulate haematopoietic development, including Stat3, Nr0b2, Ybx1 and App, and confirmed their roles using zebrafish, mouse and human models. Notably, CellComm revealed extensive crosstalk among signalling pathways and convergence on common transcriptional regulators, indicating a resilient developmental programme that ensures dynamic adaptation to changes in the embryonic environment. Our work provides an algorithm and data resource for the scientific community.

Epigenetic Factors in Eutopic Endometrium in Women with Endometriosis and Infertility.

Eutopic endometrium in patients with endometriosis is characterized by aberrant expression of essential genes during the implantation window. It predisposes to disturbance of endometrial receptivity. The pathomechanism of implantation failures in women with endometriosis remains unclear. This paper aims to summarize the knowledge on epigenetic mechanisms in eutopic endometrium in the group of patients with both endometriosis and infertility. The impaired DNA methylation patterns of gene promoter regions in eutopic tissue was established. The global profile of histone acetylation and methylation and the analysis of selected histone modifications showed significant differences in the endometrium of women with endometriosis. Aberrant expression of the proposed candidate genes may promote an unfavorable embryonic implantation environment of the endometrium due to an immunological dysfunction, inflammatory reaction, and apoptotic response in women with endometriosis. The role of the newly discovered proteins regulating gene expression, i.e., TET proteins, in endometrial pathology is not yet completely known. The cells of the eutopic endometrium in women with endometriosis contain a stable, impaired methylation pattern and a histone code. Medication targeting critical genes responsible for the aberrant gene expression pattern in eutopic endometrium may help treat infertility in women with endometriosis.