Scopus list of publications for December 24, 2023
Investigating the Relationship Between Smoking Behavior and Global Brain Volume
(2024) Biological Psychiatry Global Open Science, 4 (1), pp. 74-82.
Chang, Y.a , Thornton, V.a , Chaloemtoem, A.a , Anokhin, A.P.a , Bijsterbosch, J.b , Bogdan, R.c , Hancock, D.B.d , Johnson, E.O.e , Bierut, L.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
d Social, Statistical and Environmental Sciences, Research Triangle Institute International, Research Triangle ParkNorth Carolina, United States
e Fellow Program, Research Triangle Institute International, Research Triangle ParkNorth Carolina, United States
Abstract
Background: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate directionality: Bradford Hill’s criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis. Methods: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume. Results: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = −2964 mm3, p = 2.04 × 10−16), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10−84), but only modestly associated with total gray matter volume (effect size = −424 mm3, p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. Conclusions: A history of daily smoking is strongly associated with a decreased total brain volume. © 2023
Author Keywords
Genetics; Global brain volume; Smoking; UK Biobank
Funding details
National Institutes of HealthNIHR01MH128286
National Institute on Drug AbuseNIDAK12DA041449, R01DA044014
National Institute on Alcohol Abuse and AlcoholismNIAAAR01AA027049, U10AA008401
National Institute on AgingNIAR56AG058726
Institute of Clinical and Translational SciencesICTSR01AG061162, R01DA054750, R21AA027827, TL1TR002344, U01DA055367
McDonnell Center for Systems NeuroscienceR01AA025646, R01DA89801
Document Type: Article
Publication Stage: Final
Source: Scopus
MeCP2 represses the activity of topoisomerase IIβ in long neuronal genes
(2023) Cell Reports, 42 (12), art. no. 113538, .
Nettles, S.A., Ikeuchi, Y., Lefton, K.B., Abbasi, L., Erickson, A., Agwu, C., Papouin, T., Bonni, A., Gabel, H.W.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, detecting enrichment at regulatory regions and gene bodies of long genes, including MeCP2-regulated genes. We show that loss and overexpression of MeCP2 alter TOP2β activity at MeCP2-regulated genes. These findings uncover a mechanism of TOP2β inhibition by MeCP2 in neurons and implicate TOP2β dysregulation in disorders caused by MeCP2 disruption. © 2023 The Authors
Author Keywords
brain; CP: Neuroscience; enhancer; gene regulation; long genes; MeCP2; neurodevelopmental disorders; Rett syndrome; TOP2β; transcription
Funding details
U.S. Department of DefenseDOD28616, W911NF-21-1-0312
National Institute of Mental HealthNIMHR01MH117405
National Institute of Neurological Disorders and StrokeNINDS1R01MH127163-01, R01NS04102
Whitehall Foundation2020-08-35
Washington University in St. LouisWUSTL
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis22-3930-26275U
Genome Technology Access CenterGTAC
Document Type: Article
Publication Stage: Final
Source: Scopus
Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2
(2023) Science Signaling, 16 (815), art. no. eadi9018, .
LaPak, K.M.a , Saeidi, S.a , Bok, I.a , Wamsley, N.T.a , Plutzer, I.B.a , Bhatt, D.P.a , Luo, J.b , Ashrafi, G.a c , Major, M.B.a
a Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, United States
b Division of Public Health Sciences, Department of Surgery, WUSM and Siteman Cancer Center Biostatistics and Qualitative Research Shared Resource, Washington University, St. Louis, MO 63110, United States
c Department of Genetics, Washington University, St. Louis, MO 63110, United States
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection. Copyright © 2023 The Authors, some rights reserved.
Funding details
National Institutes of HealthNIHR01CA244236, T32CA009547-34
Document Type: Article
Publication Stage: Final
Source: Scopus