Biology subjects

Guffanti, G.

Publications and source records attributed to Guffanti, G..

3 recordsLinked to original sources

bioRxiv2025

Sex Differences in B2 SINE RNA Expression and its Role in Hippocampal Development

Once dismissed as "junk", transposable elements (TE) have recently gained recognition for their regulatory roles, notably in the brain and in development. The brain is hormone-responsive and the hippocampus in particular is sensitive to circulating gonadal hormones. While transcriptionally active, TE function remains poorly understood, especially in the brain. We and others have shown that one particular TE RNA, B2 SINE ncRNA, is a regulator in the rodent hippocampus, especially after a psychologically stressful event like acute restraint stress. It is unknown, however, if B2 SINE ncRNA is necessary for the proper development of hippocampal neurons, and furthermore, if there is a sex difference in this development. This work investigates the difference in expression of B2 SINE RNA across sexes and its role in the development of primary hippocampal neurons. We utilized pooled locked nucleic acid (LNA) GapmeRs to knock down the expression of B2 SINE RNA and treated primary hippocampal neurons with dihydrotestosterone (DHT) to test if there is a difference in dendritic complexity. We used Sholl analysis to quantify the branching, number of tips, and Sholl mean. We found a sex difference in both B2 SINE, higher in males compared to females, and {beta}-actin, lower in males compared to females. Additionally, knocking down B2 SINE RNA results in a reduction of dendritic complexity in male but not in female neurons. Taken together, this work suggests that B2 SINE RNA is expressed differentially and plays an important role in the proper development of hippocampal neurons in a sex dependent manner. Our findings support the identification of a sex-specific biomarker that may enable individualized treatment of conditions influenced by sex. This is the first evidence of the role a transposable elements RNA has in the regulation of the development of neurons and the first to show that differential regulation by sex. Summary ParagraphLong considered "junk DNA", transposable elements have gained recognition as regulators in the genome. Some of these elements are transcriptionally active and have been known to control the expression of downstream protein coding genes. Recently, murine B2 SINE RNA has been shown to regulate glucocorticoid responsive genes in the rodent hippocampus. However, it is unknown if B2 SINE RNA is necessary for the proper development of hippocampal neuron structure and if there is a sex difference in this development. Here we show that B2 SINE is higher in the male hippocampus compared to females, and knocking down B2 SINE RNA results in a reduction of dendritic complexity in male but not in female neurons. This work shows that B2 SINE RNA is expressed differentially across sexes, and that this noncoding RNA plays an important role in the development of hippocampal neurons. These findings are the first to demonstrate the role for a transposable elements RNA in the development of neuronal structure and the first to show that this is differential across sex. These findings support the identification of a sex specific biomarker that could lead to individual treatments of neurological disorders influenced by sex.

neuroscience↗

bioRxiv2019

Genomic Influences on Self-Reported Childhood Maltreatment

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to 1) identify genetic variation associated with reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n=124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35x10-8, FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24x10-8, FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be [~]6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65x10-40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. FOXP genes could influence traits such as depression and thereby be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

genomics↗

bioRxiv2019

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

Differences in susceptibility to posttraumatic stress disorder (PTSD) may be related to epigenetic differences between PTSD cases and trauma-exposed controls. Such epigenetic differences may provide insight into the biological processes underlying the disorder. Here we describe the results of the largest DNA methylation meta-analysis of PTSD to date with data from the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Ten cohorts, military and civilian, contributed blood-derived DNA methylation data (HumanMethylation450 BeadChip) from 1,896 PTSD cases (42%) and trauma-exposed controls (58%). Utilizing a common QC and analysis strategy, we identified ten CpG sites associated with PTSD (9.61E-07<p<4.72E-11) after adjustment for multiple comparisons (FDR<.05). Several CpGs were located in genes previously implicated in PTSD and other psychiatric disorders. The top four CpG sites fell within the aryl-hydrocarbon receptor repressor (AHRR) locus and were associated with lower DNA methylation in PTSD cases relative to controls. Interestingly, this association appeared to uncorrelated with smoking status and was most pronounced in non-smokers with PTSD. Additional evaluation of metabolomics data supported our findings and revealed that AHRR methylation associated with kynurenine levels, which were lower among subjects with PTSD relative to controls. Overall, this study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

genomics↗