Biology subjects

Breen, M. S.

Publications and source records attributed to Breen, M. S..

4 recordsLinked to original sources

bioRxiv2018

Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.\n\nSignificance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.

neuroscience↗

bioRxiv2017

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes

Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n=20), depression (n=31) and PTSD with comorbid depression (n=13), compared to carefully matched trauma exposed controls (n=23) and healthy mothers (n=62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.

developmental biology↗

bioRxiv2017

Insights into the molecular changes associated with postnatal human brain development: an integrated transcriptomics and proteomics study

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR p < 0.05). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH-metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation and disease.

neuroscience↗

bioRxiv2017

PTSD Blood Transcriptome Mega-Analysis: Shared Inflammatory Pathways Across Genders And Modes Of Traumas

Transcriptome-wide screens of peripheral blood during the onset and development of posttraumatic stress disorder (PTSD) indicate widespread immune dysregulation. However, little is known as to whether biological sex and the type of traumatic event influence shared or distinct biological pathways in PTSD. We performed a combined analysis of five independent PTSD blood transcriptome studies covering seven types of trauma in 229 PTSD and 311 comparison individuals to synthesize the extant data. Analyses by trauma type revealed a clear pattern of PTSD gene expression signatures distinguishing interpersonal (IP)-related traumas from combat-related traumas. Co-expression network analyses integrated all data and identified distinct gene expression perturbations across sex and modes of trauma in PTSD, including one wound-healing module down-regulated in men exposed to combat traumas, one IL12-mediated signaling module up-regulated in men exposed to IP-related traumas, and two modules associated with lipid metabolism and MAPK-activity up-regulated in women exposed to IP-related traumas. Remarkably, a high degree of sharing of transcriptional dysregulation across sex and modes of trauma in PTSD was also observed converging on common signaling cascades, including cytokine, innate immune and type I interferon pathways. Collectively, these findings provide a broad view of immune dysregulation in PTSD and demonstrate inflammatory pathways of molecular convergence and specificity, which may inform mechanisms and diagnostic biomarkers for the disorder.

neuroscience↗