Genomic Psychiatry Early Online Release

Stress significantly impacts brain function and is a major contributor to major depressive disorder. This study explores the role of long noncoding RNAs (lncRNAs) in stress-induced chromatin remodeling and gene regulation, particularly in the context of glucocorticoid receptor (GR) activation, a hallmark of stress-related disorders. Using a cellular model, GR activation regulated 79 lncRNAs: 44 upregulated and 35 downregulated. Chromosome-wise analyses of lncRNA regulation revealed complex patterns, with specific chromosomes, chr1 and chr15, showing a higher prevalence of downregulated genes, while chr11 and chr12 exhibited upregulated genes, indicating the differential roles of lncRNAs in gene silencing and activation. The differentially regulated lncRNAs were further classified into intergenic, overlap_antisense and overlap_sense, revealing their diverse roles in regulating gene expression. An immunoprecipitated ribonucleoprotein assay followed by sequencing confirmed the interaction of lncRNAs with a histone methyltransferase primarily targeting histone H3 lysine 27 (H3K27), with 87 lncRNAs enriched in the pull-down group, and 51 enriched in the EZH2 pull-down, a part of Polycomb Repressive Complex 2 (PRC2), linking these lncRNAs to PRC2-mediated chromatin repression. An integrative analysis revealed an inverse correlation between specific lncRNAs and the transcriptional activity of proximal genes, supporting the role of lncRNAs in gene silencing. Gene ontology of suppressed genes highlighted enrichment in functions related to neuronal death and synaptic transmission. Altogether, our study demonstrates that lncRNAs, particularly those interacting with PRC2, may serve as potential mediators of stress-induced neuronal changes by influencing chromatin accessibility, and potentially highlight their roles in stress-related disorders.

Introduction

Long noncoding RNAs (lncRNAs) are lengthy RNA molecules (more than 200 nucleotides) that are not translated into proteins. These molecules are precise regulators of gene action, activating or silencing genes and influencing the chromatin structure that packages DNA in the nucleus. In this way, lncRNAs contribute to the upregulation or suppression of genes that activate, develop, or adapt the neuronal signalling apparatus in response to cellular stress (1).

Figure 1.Molecular pathway linking chronic stress to major depressive disorder through lncRNA-mediated chromatin silencing. Chronic stress activates the HPA axis, elevating glucocorticoid levels and triggering nuclear translocation of

Citation: Genomic Psychiatry 2025; 10.61373/gp025d.0110

Download as Powerpoint
Download Figure

Bruce M. Cohen, MD, PhD, stands as one of psychiatry's most innovative research leaders, transforming our understanding of neuropsychiatric disorders through groundbreaking multidisciplinary approaches at McLean Hospital and Harvard Medical School. As Robertson-Steele Professor of Psychiatry at Harvard and Director of the Program for Neuropsychiatric Research at McLean Hospital, Dr. Cohen has pioneered revolutionary techniques combining brain imaging, genomics, and induced pluripotent stem cell models to unlock the complex biological mechanisms underlying schizophrenia, bipolar disorder, and Alzheimer's disease. With over 400 peer-reviewed publications and five awarded patents spanning nearly five decades at McLean, his discoveries in mitochondrial dysfunction and energy metabolism abnormalities have opened unprecedented therapeutic pathways. His laboratory's cutting-edge ability to grow brain cells from patient samples represents what he describes as technology "giving us leads we did not have forty years ago." Named Psychiatrist of the Year twice by the National Alliance on Mental Illness of Massachusetts, Dr. Cohen's impact extends beyond research to institutional transformation. As McLean's President from 1997 to 2005, he reversed the hospital's financial decline, establishing over 30 new programs while achieving record levels of patient care, research funding, and educational training. His current work challenges century-old psychiatric diagnostic models with evidence-based dimensional approaches that better capture the complexity of mental illness. In this comprehensive Genomic Press Interview, Dr. Cohen shares insights from his remarkable journey from molecular genetics at MIT and Case Western to becoming a leading voice advocating for the replacement of stigmatizing terms like "schizophrenia" with scientifically accurate alternatives, while revealing the personal experiences and intellectual curiosity that have driven his dedication to understanding and treating the most challenging neuropsychiatric conditions.

Dr. Najaf Amin stands at the forefront of depression genetics research, revolutionizing our understanding of major depression through groundbreaking multi-omics approaches that bridge molecular epidemiology and neuropsychiatry. In this exclusive Genomic Press Interview, the Oxford University Associate Professor shares insights from a career that has positioned her among the top top scientists globally and top women in science worldwide. With over 350 peer-reviewed publications and an exceptional h-index of 125, Dr. Amin's pioneering work has fundamentally challenged conventional paradigms in the field of depression research. Her landmark discovery of the RCL1 gene mutation and its connection to primate-specific interlaminar astrocytes opened entirely new avenues for understanding the pathogenesis of depression. Leading the most extensive published studies on epigenomics, metabolomics, and gut microbiome in major depression, including groundbreaking research in Nature Communications (2022) and JAMA Psychiatry (2023), she has identified 124 metabolites associated with depression, with 49 being novel discoveries. Dr. Amin's integrative approach encompasses genomics, transcriptomics, proteomics, and single-cell analysis, providing unprecedented molecular insights into depression that extend beyond traditional genetic frameworks. Her journey from Pakistan to becoming a leading voice in molecular epidemiology at Oxford exemplifies resilience, scientific excellence, and the transformative power of perseverance in advancing our understanding of one of humanity's most complex psychiatric disorders.

Role of lncRNAs in stress-associated gene regulation following chromatin silencing: Mechanistic insights from an in vitro cellular model of glucocorticoid receptor gene overexpression

Stress, chromatin, and long noncoding RNA: A new frontier in psychiatric biology

Introduction

Bruce M. Cohen: An eclectic life and a multidisciplinary approach to the complex determinants and diverse presentations of psychiatric disorders

Najaf Amin: Rare coding genetic variation and downstream omics hold the key to understanding the pathogenesis of depression

Martin Alda: Deciphering heterogeneity: The key to personalized psychiatry

Gerhard Andersson: Innovating psychotherapy research by using the internet

Oliver Pain: Bringing together functional and statistical genomics to enhance personalised medicine for neuropsychiatric disorders

Miguel E. Rentería: At the intersection of genomics, neuroscience, and big data

Alexander W. Charney: Leveraging genomics to advance the treatment of mental illness

Mirko Manchia: Exploring the biological landscape of psychiatric disorders to innovate clinical management with precision medicine approaches

Eric Sun: Understanding brain aging at spatial and single-cell resolution with machine learning

Prader-Willi syndrome: Genetics, clinical symptoms, and model systems

Yehezkel Ben-Ari: The Neuroarcheology concept: From brain development to predicting, understanding, and treating brain disorders

Adenosine as the metabolic common path of rapid antidepressant action: The coffee paradox

Table of Contents

Cover-to-Cover

Table of Contents

Cover-to-Cover

Table of Contents

Yogesh Dwivedi: Pre-clinical and translational research focusing on gene regulation through epigenetic and epitranscriptomic mechanisms and their implications in mood disorders and suicidal behavior

Oliver Pain: Bringing together functional and statistical genomics to enhance personalised medicine for neuropsychiatric disorders

Cover-to-Cover

Cover-to-Cover