Biology subjects

McLaughlin, K. A.

Publications and source records attributed to McLaughlin, K. A..

8 recordsLinked to original sources

bioRxiv2021

Nucleosomal Asymmetry Shapes Histone Mark Binding and Promotes Poising at Bivalent Domains

Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one mark. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, despite presence of H3K4me3, thereby promoting a poised state. Strikingly, the bivalent mark combination further attracts chromatin proteins that are not recruited by each mark individually, including the histone acetyltransferase complex KAT6B (MORF). Knockout of KAT6B blocks neuronal differentiation, demonstrating that bivalency-specific readers are critical for proper ESC differentiation. These findings reveal how histone mark bivalency directly promotes establishment of a poised state at developmental genes, while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.

molecular biology↗

bioRxiv2020

Smaller Hippocampal Volume among Black and Latinx Youth Living in High-Stigma Contexts

BackgroundTo determine whether being raised in a stigmatizing context influences neurodevelopment in children. MethodsWe drew data from one of the first national, multi-site neuroimaging studies with substantial variability in sociopolitical contexts: the Adolescent Brain and Cognitive Development study (N=11,534; M=9.9 years). We measured structural stigma surrounding gender, race, and Latinx ethnicity using objective state-level indicators of social policies and prejudicial attitudes and individual-level experiences of perceived discrimination, and examined associations with two neural markers: hippocampal volume and amygdala reactivity to threat. ResultsIn a pre-registered analysis, we find that Black (B=-57.27, p=0.025) and Latinx (B=-41.02, p=0.037) youths raised in higher-stigma environments have smaller hippocampal volume than youths raised in low-stigma contexts, controlling for demographics and family socioeconomic status. This association was marginal among girls (p=0.082). The magnitude of the observed difference in hippocampal volume between high and low structural stigma contexts was equivalent to a $20,000 difference in annual family income. Stigmatizing environments were unrelated to hippocampal volume in non-stigmatized youth, providing evidence of specificity. Perceived discrimination was unrelated to hippocampal volume among any of the stigmatized groups. No associations between individual or structural forms of stigma and amygdala reactivity to threat were observed in the stigmatized groups. ConclusionsWe provide novel evidence that an objective measure of stigma at the contextual level (structural stigma) may have a stronger influence on neurodevelopment than subjective perceptions of stigma measured at the individual level, suggesting that contextual approaches may yield new insights into neurodevelopment.

neuroscience↗

bioRxiv2020

Cross-sectional and longitudinal associations of threat and deprivation on cognition, emotional processing and psychopathology in children and adolescents

BackgroundExposure to childhood adversity has been consistently associated with poor developmental outcomes, but it is unclear whether these associations vary across different forms of adversity. We examined cross-sectional and longitudinal associations between two types of adversity--threat and deprivation--with cognition, emotional processing, and psychopathology in a middle-income country. MethodsThe sample consisted of 2,511 children and adolescents (6-17 years old) from the Brazilian High-Risk Cohort for Psychiatric Disorders. Parent reports on childhood adversity were used to construct threat and deprivation latent constructs. Psychopathology was measured by the CBCL which generated a measure of general psychopathology (the "p" factor). Executive function (EF) and attention orienting toward angry faces were assessed using cognitive tasks. All measures were acquired at two time-points 3-years apart. Cross-lagged panel models were estimated to evaluate longitudinal associations. ResultsPsychopathology was associated with threat and deprivation cross-sectionally, and higher levels of threat and deprivation predicted increases in general psychopathology at follow-up. For EF, worse performance was more strongly associated with deprivation than threat at baseline, and only with deprivation at follow-up. Deprivation was associated with attention orienting away from angry faces cross-sectionally, but neither form of adversity was associated with changes over time in attention bias. ConclusionBoth types of adversity are associated with current and future psychopathology and with current, but not future, EF. Threat was more strongly linked to higher psychopathology, whereas deprivation was more strongly linked to lower EF. Lack of longitudinal associations between deprivation and EF mean reverse causality cannot be excluded.

neuroscience↗

bioRxiv2019

Reduced Hippocampal and Amygdala Volumes as Mechanisms of Stress Sensitization to Depression following Childhood Violence Exposure

OBJECTIVEStressful life events are more likely to trigger depression among individuals exposed to childhood adversity. However, the mechanisms underlying this stress sensitization remain largely unknown. Any such mechanism must be altered by childhood adversity and interact with recent stressful life events, magnifying their association with depression. This study investigated whether reduced hippocampal and amygdala volumes are mechanisms of stress sensitization following childhood violence exposure.\n\nMETHODSA sample of 149 youth (aged 8-17 years), with (N=76) and without (N=73) exposure to physical abuse, sexual abuse, or domestic violence participated. Participants completed a structural MRI scan and were assessed for symptoms of depression. Approximately two years later, stressful life events were assessed along with depression symptoms in 120 participants (57 violence-exposed).\n\nRESULTSChildhood violence exposure was associated with smaller hippocampal and amygdala volumes. Stressful life events occurring during the follow-up period predicted worsening depression over time, and this association was magnified among those with smaller hippocampal and amygdala volumes. Significant moderated mediation models revealed indirect effects of violence exposure on increasing depression over time through hippocampal and amygdala volumes, particularly among youths who experienced more stressful life events.\n\nCONCLUSIONSThese results provide novel evidence for reduced hippocampal and amygdala volumes as mechanisms of stress sensitization to depression following exposure to violence. These findings suggest that hippocampal and amygdala-mediated emotional and cognitive processes may contribute to vulnerability to stressful life events following childhood violence exposure.

neuroscience↗

bioRxiv2019

Characterizing the Network Architecture of Emotion Regulation Neurodevelopment

The ability to regulate emotions is key to goal attainment and wellbeing. Although much has been discovered about how the human brain develops to support the acquisition of emotion regulation, very little of this work has leveraged information encoded in whole-brain networks. Here we employed a network neuroscience framework to parse the neural underpinnings of emotion regulation skill acquisition while accounting for age in a sample of youth (N = 70, 34 female). Focusing on three key network metrics--network differentiation, modularity, and community structure differences between active regulation and a passive emotional baseline--we found that the control network, the default mode network, and limbic network were each related to emotion regulation ability while controlling for chronological age. Greater network differentiation in the control and limbic networks was related to better emotion regulation ability. With regards to network community structure, more communities and more crosstalk between modules (i.e., less modularity) in the control network were associated with better regulatory ability. By contrast, less crosstalk (i.e., more modularity) between modules in the default mode network was associated with better regulatory ability. Together, these findings highlight possible whole-brain connectome features that support the acquisition of emotion regulation in youth.

neuroscience↗

bioRxiv2019

Biological Aging in Childhood and Adolescence Following Experiences of Threat and Deprivation: A Systematic Review and Meta-Analysis

Life history theory argues that exposure to early-life adversity (ELA) accelerates development, although existing evidence for this varies. We present a meta-analysis and systematic review testing the hypothesis that ELA involving threat (e.g., violence exposure) will be associated with accelerated biological aging across multiple metrics, whereas exposure to deprivation (e.g., neglect, institutional rearing) and low-socioeconomic status (SES) will not. We meta-analyze 46 studies (n=64,925) examining associations of ELA with pubertal timing and cellular aging (telomere length and DNA methylation age), systematically review 19 studies (n=2276) examining ELA and neural markers of accelerated development (cortical thickness and amygdala-prefrontal cortex functional connectivity) and evaluate whether associations of ELA with biological aging vary according to the nature of adversity experienced. ELA overall was associated with accelerated pubertal timing (d=-0.12) and cellular aging (d=-0.32). Moderator analysis revealed that ELA characterized by threat (d=-0.26), but not deprivation or SES, was associated with accelerated pubertal development. Similarly, exposure to threat-related ELA was associated with accelerated cellular aging (d=-0.43), but not deprivation or SES. Systematic review revealed associations between ELA and accelerated cortical thinning, with threat-related ELA consistently associated with thinning in ventromedial prefrontal cortex, and deprivation and SES associated with thinning in frontoparietal, default, and visual networks. There was no consistent association of ELA with amygdala-PFC connectivity. These findings suggest specificity in the types of early environmental experiences associated with accelerated biological aging and highlight the importance of evaluating how accelerated aging contributes to health disparities and whether this process can be mitigated through early intervention.

neuroscience↗

bioRxiv2019

DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

cell biology↗

bioRxiv2018

Spatial and Temporal Cortical Variability Track with Age and Affective Experience During Emotion Regulation in Youth

Variability is a fundamental feature of human brain activity that is particularly pronounced during development. However, developmental neuroimaging research has only recently begun to move beyond characterizing brain function exclusively in terms of magnitude of neural activation to incorporate estimates of variability. No prior neuroimaging study has done so in the domain of emotion regulation. We investigated how age and affective experiences relate to spatial and temporal variability in neural activity during emotion regulation. In the current study, 70 typically developing youth aged 8-17 years completed a cognitive reappraisal task of emotion regulation while undergoing functional magnetic resonance imaging. Estimates of spatial and temporal variability during regulation were calculated across a network of brain regions, defined a priori, and were then related to age and affective experiences. Results showed that increasing age was associated with reduced spatial and temporal variability in a set of frontoparietal regions (e.g., dorsomedial prefrontal cortex, superior parietal lobule) known to be involved in effortful emotion regulation. In addition, youth who reported less negative affect during regulation had less spatial variability in the ventrolateral prefrontal cortex, which has previously been linked to cognitive reappraisal. We interpret age-related reductions in spatial and temporal variability as implying neural specialization. These results suggest that the development of emotion regulation is undergirded by a process of neural specialization and open up a host of possibilities for incorporating neural variability into the study of emotion regulation development.

neuroscience↗