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<p>Chromatin conformational changes are key to gene regulation in the brain and have recently been shown to be regulated by super-enhancer RNAs (seRNAs). We examine the role of seRNAs in major depressive disorder (MDD) by profiling the prefrontal cortex from 25 MDD subjects and 25 matched non-psychiatric controls. Our analysis reveals 175 differentially expressed seRNAs, of which 140 are&#xa0;upregulated and 35 are&#xa0;downregulated. Our proximity mapping (±50 kb) links 94 seRNAs to nearby protein-coding genes, while long-range analysis (±500 kb) uncovered 584 seRNA–mRNA interaction pairs, most within 400 kb of genomic range. These interactions formed cis-regulatory hubs and hotspots, with notable pairs involving <i>CEBPA, NR3C1</i>, and <i>DUSP1</i>. Additionally, several genes are found to be co-regulated by distinct seRNAs. Spatial mapping confirms that many altered seRNAs are located near super-enhancer regions. Our results for the first time highlight seRNAs as key modulators of proximal and distal gene networks in MDD, offering novel insights and therapeutic avenues.</p><p></p>

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Super Enhancer RNAs Rewrite the Molecular Script of Complex Gene Regulation in the MDD Brain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Yogesh Dwivedi,
  • Bhaskar Roy

摘要

Chromatin conformational changes are key to gene regulation in the brain and have recently been shown to be regulated by super-enhancer RNAs (seRNAs). We examine the role of seRNAs in major depressive disorder (MDD) by profiling the prefrontal cortex from 25 MDD subjects and 25 matched non-psychiatric controls. Our analysis reveals 175 differentially expressed seRNAs, of which 140 are upregulated and 35 are downregulated. Our proximity mapping (±50 kb) links 94 seRNAs to nearby protein-coding genes, while long-range analysis (±500 kb) uncovered 584 seRNA–mRNA interaction pairs, most within 400 kb of genomic range. These interactions formed cis-regulatory hubs and hotspots, with notable pairs involving CEBPA, NR3C1, and DUSP1. Additionally, several genes are found to be co-regulated by distinct seRNAs. Spatial mapping confirms that many altered seRNAs are located near super-enhancer regions. Our results for the first time highlight seRNAs as key modulators of proximal and distal gene networks in MDD, offering novel insights and therapeutic avenues.