Biology subjects

Muglia, L. J.

Publications and source records attributed to Muglia, L. J..

9 recordsLinked to original sources

bioRxiv2022

A Genome Scale Transcriptional Regulatory Model of the Human Placenta

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

systems biology↗

bioRxiv2022

GTAGMe-seq: joint profiling of genetic variants, DNA methylation, GpC methyltransferase footprints, and 3D genome in the same DNA molecules

Cis-regulatory elements coordinate the regulation of their targeted genes expression. However, the joint measurement of cis-regulatory elements activities and their interactions in spatial proximity is limited by the current sequencing approaches. We describe a method, NOMe-HiC, which simultaneously captures single nucleotide polymorphisms, DNA methylation, chromatin accessibility (GpC methyltransferase footprints), and chromosome conformation changes from the same DNA molecule, together with the transcriptome, in a single assay. NOMe-HiC shows high concordance with state-of-the-art mono-omic assays across different molecular measurements and reveals coordinated chromatin accessibility at distal genomic segments in spatial proximity and novel types of long-range allele-specific chromatin accessibility.

genomics↗

bioRxiv2021

Characterization of methylation signatures in spontaneous preterm birth

Preterm birth is a global public health crisis which results in significant neonatal and maternal mortality. Yet little is known regarding the molecular mechanisms of idiopathic spontaneous preterm birth, and we have few diagnostic markers for adequate assessment of placental development and function. Previous studies of placental pathology and our transcriptomics studies suggest a role for placental maturity in idiopathic spontaneous preterm birth. It is known that placental DNA methylation changes over gestation. We hypothesized that if placental hypermaturity is present in our samples, we would observe a unique idiopathic spontaneous preterm birth DNA methylation profile potentially driving the gene expression differences we previously identified in our placental samples. Our results indicate the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern suggesting hypermaturity. Only seven significant differentially methylated regions fitting the idiopathic spontaneous preterm birth specific (relative to the controls) profile were identified, indicating unusually high similarity in DNA methylation between idiopathic spontaneous preterm birth and term birth samples. We identified an additional 1,718 significantly methylated regions in our gestational age matched controls were the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern, again indicating a striking level of similarity between the idiopathic spontaneous preterm birth and term birth samples. Pathway analysis of these regions revealed differences in genes within the WNT and Cadherin signaling pathways, both of which are essential in placental development and maturation. Taken together, these data demonstrate that the idiopathic spontaneous preterm birth samples are molecularly more mature than expected given their respective gestational age which likely impacts birth timing.

physiology↗

bioRxiv2020

Prenatal psychosocial stress-induced behavioral and neuroendocrine abnormalities are associated with sex-specific alterations in synaptic transmission and differentially modulated by maternal environment

Prenatal stress (PS) is associated with increased vulnerability to affective disorders. Transplacental glucocorticoid passage and stress-induced maternal environment alterations are recognized as potential routes of transmission that can fundamentally alter neurodevelopment. However, molecular mechanisms underlying aberrant emotional outcomes or the individual contributions intrauterine stress versus maternal environment play in shaping these mechanisms remain unknown. Here, we report anxiogenic behaviors, anhedonia, and female hypothalamic-pituitary-adrenal axis hyperactivity as a consequence of psychosocial PS in mice. Sex-specific placental responses to stress and evidence of fetal amygdala programming precede these abnormalities. In adult offspring, we observe amygdalar transcriptional changes demonstrating sex-specific dysfunction in synaptic transmission and neurotransmitter systems. We find these abnormalities are primarily driven by in-utero stress exposure. Importantly, maternal care changes postnatally reverse anxiety-related behaviors and partially rescue gene alterations associated with neurotransmission. Our data demonstrate the influence maternal environment exerts in shaping offspring emotional development despite deleterious effects of intrauterine stress.

neuroscience↗

bioRxiv2020

Haplotype-based heritability estimations reveal gestational duration as a maternal trait and fetal size measurements at birth as fetal traits in human pregnancy

AbstractGenotype-based approaches for the estimation of SNP-based narrow-sense heritability [Formula] have limited utility in pregnancy-related outcomes due to confounding by the shared alleles between mother and child. Here, we propose a haplotype-based approach to estimate the genetic variance attributable to three haplotypes - maternal transmitted [Formula], maternal non-transmitted [Formula] and paternal transmitted [Formula] in mother-child pairs. We show through extensive simulations that our haplotype-based approach outperforms the conventional and contemporary approaches for resolving the contribution of maternal and fetal effects, particularly when m1 and p1 have different effects in the offspring. We apply this approach to estimate the explicit and relative maternal-fetal genetic contribution to the phenotypic variance of gestational duration and gestational duration adjusted fetal size measurements at birth in 10,375 mother-child pairs. The results reveal that variance of gestational duration is mainly attributable to m1 and m2 ([Formula]= 17.3%, S. E. = 5.2%; [Formula] = 12.2%, S. E. = 5.2%; [Formula] = 0.0%, S. E. = 5.0%). In contrast, variance of fetal size measurements at birth are mainly attributable to m1 and p1 ([Formula] = 18.6 - 36.4%, [Formula] = 0.0 - 5.2% and [Formula] = 4.4 - 13.6%). Our results suggest that gestational duration and fetal size measurements are primarily genetically determined by the maternal and fetal genomes, respectively. In addition, a greater contribution of m1 as compared to m2 and p1 [Formula] to birth length and head circumference suggests a substantial influence of correlated maternal-fetal genetic effects on these traits. Our newly developed approach provides a direct and robust alternative for resolving explicit maternal and fetal genetic contributions to the phenotypic variance of pregnancy-related outcomes.

genetics↗

bioRxiv2020

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

genomics↗

bioRxiv2019

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. However, there is no framework to comprehensively evaluate how these traits evolved or to explore the relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we develop an approach to test for signatures of diverse evolutionary forces, including multiple types of selection, and apply it to genomic regions associated with spontaneous preterm birth (sPTB), a complex disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary signatures including evolutionary sequence conservation (consistent with the action of negative selection), excess population differentiation (local adaptation), accelerated evolution (positive selection), and balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop hypotheses about how these genomic regions contribute to sPTB risk. In summary, we introduce an approach for inferring the spectrum of evolutionary forces acting on genomic regions associated with complex disorders. When applied to sPTB-associated genomic regions, this approach both improves our understanding of the potential roles of these regions in pathology and illuminates the mosaic nature of evolutionary forces acting on genomic regions associated with sPTB.

evolutionary biology↗

bioRxiv2019

Haplotype genetic score analysis in 10,734 mother/infant pairs reveals complex maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes and adult phenotypes

Many maternal traits are associated with a neonates gestational duration, birth weight and birth length. These birth outcomes are subsequently associated with late onset health conditions. Based on 10,734 mother/infant duos of European ancestry, we constructed haplotype genetic scores to dissect the maternal and fetal genetic effects underlying these observed associations. We showed that maternal height and fetal growth jointly affect the duration of gestation - maternal height positively influences the gestational duration, while faster fetal growth reduces gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: tall maternal stature and higher blood glucose causally increase birth size; in the fetus, the height and metabolic risk increasing alleles can lead to increased and decreased birth size respectively; birth weight-raising alleles in fetus may reduce gestational duration and increase maternal blood pressure. These maternal and fetal genetic effects can largely explain the observed associations between the studied maternal phenotypes and birth outcomes as well as the life-course associations between these birth outcomes and adult phenotypes.

genetics↗

bioRxiv2018

Assessing placental maturity through histological and transcriptomic analyses in idiopathic spontaneous preterm birth

Preterm birth (PTB) is leading contributor to infant death in the United States and globally, yet the underlying mechanistic causes are not well understood. Histopathological studies of preterm birth suggest advanced villous maturity may have a role in idiopathic spontaneous preterm birth (isPTB). To better understand pathological and molecular basis of isPTB, we compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB between 28-36 weeks gestation and healthy term placentasu. Transcriptomic analyses revealed a unique expression signature for isPTB distinct from the age-matched controls that were delivered prematurely due to infection. This signature included the upregulation of three IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB. However, within the isPTB expression signature, we detected secondary signature of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the gestational age-matched infected samples included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth.

developmental biology↗