Biology subjects

Notterman, D. A.

Publications and source records attributed to Notterman, D. A..

4 recordsLinked to original sources

bioRxiv2026

Differential Methylation by Early Life Adversity in the Future of Families Child Wellbeing Study

Early life adversity (ELA) has a well-established link to mental health disorders later in life, yet the molecular mechanisms behind this relationship are incompletely understood. The Future of Families Child Wellbeing Study (FFCWS) provides an opportunity to examine experience encoding in the genome through functional changes in DNA methylation (DNAm) in a cohort enriched in subjects exposed to ELA. We investigated epigenome-wide differences in DNAm across thirteen early-life exposures in salivary samples from FFCWS participants. We calculated differential methylation associations with disease-linked genetic variants, evaluated tissue-specific gene expression, and assessed the persistence of DNAm changes from ages 9 to 15 years. Using data from the mSTARR-seq assay, we characterized methylation-dependent regulatory activity. Differential methylation in the FFCWS validated prior results and identified new genomic regions associated with child adversity. Differential methylation occurs in genomic regions likely to impact gene expression, and affected genes are expressed in disease-relevant tissues. We also identified association of genetic variants associated with downstream disorders near differential methylation, including depression, alcohol and substance use, and anxiety disorders. Overall, cumulative ELA is associated with specific DNAm changes, functional regulation, and persistence over time. Our findings indicate that ELA-associated differential methylation in the FFCWS does not simply occur at random, but in genomic regions that are functional. Our results support the conclusion that altered DNAm represents a biological link between early life experience and later health outcomes.

genomics↗

bioRxiv2026

Modeling Sex Differences and Neurodegeneration in Repetitive Traumatic Brain Injury Using Drosophila

Traumatic brain injury (TBI) is a public health burden with short-term and long-term consequences for those who survive. Repetitive TBI (rTBI) is highly associated with neurodegenerative diseases such as chronic traumatic encephalopathy. Here, we present a force-adjustable, enhanced CO2-driven Drosophila model of rTBI to investigate locomotor, cognitive, proteomic, and neurodegenerative changes following rTBI. Injured males demonstrate dose-dependent locomotor deficits, while injured females display greater tolerance to rTBI. However, both sexes exhibit significant decision-making deficits. Proteomic analysis revealed changes in proteins linked with locomotory behavior, mitochondria, and energy production post-injury, correlating with observed behavioral phenotypes. Histological analysis revealed increased vacuolization area in rTBI flies. These results suggest that rTBI drives sex-specific behavioral deficits, proteomic disruption, and neurodegeneration. Overall, this enhanced Drosophila rTBI model provides a valuable tool for exploring sexually dimorphic outcomes and understanding the long-term pathophysiology of repetitive brain trauma in the context of neurodegenerative disease. Significance StatementRepetitive traumatic brain injury (rTBI) is linked to long-term cognitive decline and neurodegeneration, yet standardized, scalable models that capture sex-dependent outcomes are limited. We developed an automated, force-adjustable, closed-head Drosophila rTBI apparatus that delivers reproducible injuries without off-target damage, enabling precise control of injury severity across sexes. Using this platform, we show sexually dimorphic survival and locomotor vulnerability, persistent decision-making deficits, and progressive brain pathology marked by vacuolization and apoptosis. Proteomic profiling reveals time-dependent, sex-specific disruption of mitochondrial, oxidative stress, and locomotor-related protein networks, providing mechanistic entry points for discovering modifiers and therapies for repetitive brain trauma.

molecular biology↗

bioRxiv2023

Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence

Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female, mean age=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS). We found that salivary epigenetic-BMI is robustly associated with childrens BMI (r=0.36 to r=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence. We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.

genomics↗

bioRxiv2021

Differentially methylated regions and methylation QTLs for teen depression and early puberty in the Fragile Families Child Wellbeing Study

AO_SCPLOWBSTRACTC_SCPLOWThe Fragile Families Child Wellbeing Study (FFCWS) is a longitudinal cohort of ethnically diverse and primarily low socioeconomic status children and their families in the U.S. Here, we analyze DNA methylation data collected from 748 FFCWS participants in two waves of this study, corresponding to participant ages 9 and 15. Our primary goal is to leverage the DNA methylation data from these two time points to study methylation associated with two key traits in adolescent health that are over-represented in these data: Early puberty and teen depression. We first identify differentially methylated regions (DMRs) for depression and early puberty. We then identify DMRs for the interaction effects between these two conditions and age by including interaction terms in our regression models to understand how age-related changes in methylation are influenced by depression or early puberty. Next, we identify methylation quantitative trait loci (meQTLs) using genotype data from the participants. We also identify meQTLs with epistatic effects with depression and early puberty. We find enrichment of our interaction meQTLs with functional categories of the genome that contribute to the heritability of co-morbid complex diseases. We replicate our meQTLs in data from the GoDMC study. This work leverages the important focus of the FFCWS data on disadvantaged children to shed light on the methylation states associated with teen depression and early puberty, and on how genetic regulation of methylation is affected in adolescents with these two conditions.

genomics↗