Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

Abstract

Chorioamnionitis is an intrauterine infection involving inflammation of the chorion, amnion and placenta. It leads to a fetal systemic inflammatory response that can alter the transcription of neonatal immune genes. We have previously shown that neonatal monocytes gain the activating histone tail modification H3K4me3 at promoters of immunologically important genes as development progresses from preterm neonate to adult. In this study, we applied ChIP-seq and RNA-seq to evaluate the impact of chorioamnionitis on the neonatal monocyte H3K4me3 histone modification landscape over the course of fetal and neonatal immune system development. Chorioamnionitis exposure in neonatal monocytes resulted in a net increase in total monocyte H3K4me3, primarily in introns and intergenic regions. Immune gene expression was decreased in chorioamnionitis-exposed monocytes, with the majority of enriched transcripts falling into pathways that are not linked to the immune system. Over half of all neonatal monocyte H3K4me3 peaks, independent of their location, were associated with active gene transcription. Overall, chorioamnionitis exposure resulted in global remodeling of the neonatal monocyte H3K4me3 landscape and changes in the expression of known immune genes. These changes resulted in a less robust inflammatory response upon exposure to a secondary challenge, which may explain why chorioamnionitis-exposed neonates have an increased risk of sepsis.

Intrauterine programming of obesity and type 2 diabetes

“…Together, these studies highlight a close relationship between hyperglycaemia and inflammatory memory [23]. Infections in pregnancy, such as premature births with chorioamnionitis, have been associated with histone modification changes in cord-blood monocytes [24], and inflammation memory in vitro is epigenetically modulated [25] and reversible [26]. These findings indicate that infection in utero can alter epigenetic patterns in offspring cells, supporting a causal link between infection and offspring obesity, mediated by metabolic and epigenetic reprogramming.…”

Pulmonary Consequences of Prenatal Inflammatory Exposures: Clinical Perspective and Review of Basic Immunological Mechanisms

“…Indeed, RNAseq analyses of chorioamnionitis-exposed monocytes that were stimulated in vitro with Staphylococcus epidermidis uncovered a distinct transcriptional profile of hypo-responsiveness (127). In addition, chorioamnionitis exposure in preterm infants has also been shown to increase monocytic H3K4me3 methylation marks, which are tightly associated with inactive gene promoters (132). Monocytes from chorioamnionitis-exposed term infants with increased H3K4me3 modifications produced less IL-1β, IL-6, and IL-8 when stimulated with LPS (132).…”

“…In addition, chorioamnionitis exposure in preterm infants has also been shown to increase monocytic H3K4me3 methylation marks, which are tightly associated with inactive gene promoters (132). Monocytes from chorioamnionitis-exposed term infants with increased H3K4me3 modifications produced less IL-1β, IL-6, and IL-8 when stimulated with LPS (132). These data are also in agreement with animal models of chorioamnionitis, which documented that intra-amniotic LPS induces maturation of fetal monocyte function, but long-term or repeated exposures to either LPS or U. parvum appear to drive ex vivo hypo-responsiveness (133,134).…”

Genome‐wide postnatal changes in immunity following fetal inflammatory response

“…In umbilical cord blood monocytes from very preterm newborns (GA 29–32 weeks) affected by chorioamnionitis, it has been described the downregulation of genes involved in adaptive immunity upon monocyte stimulation with Staphylococcus epidermidis [58], the most common cause of neonatal late‐onset sepsis. The exposure of umbilical cord blood monocytes to chorioamnionitis has been also shown to alter the histone modification landscape and reduce the immune response to a second inflammatory stimulus with lipopolysaccharides [59]. The molecular events underlying this chorioamnionitis‐induced immunosuppression are, however, not well characterized in extremely preterm newborns, particularly after birth.…”