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<p>During mouse embryonic brain development, the <i>Evf2</i> ultraconserved enhancer (UCE) lncRNA guides the <i>Dlx5/6UCE</i> to ~129 sites across chr6. However, previous work identified only 4 transcriptionally regulated targets associated with <i>Evf2</i>-<i>Dlx5/6UCE</i>-gene guidance, raising questions about the significance of <i>Evf2</i>-regulated <i>Dlx5/6UCE</i>-gene interactions. Here, single-cell transcriptomics reveal far greater alignment between <i>Evf2</i>-<i>Dlx5/6UCE</i>-gene guidance and transcriptional regulation than previously reported. <i>Evf2</i> divides chr6 into short-range ( &lt;10 Mb distant), activated genes, and long/super-long-range (10-129 Mb distant), repressed genes, identifying seizure regulating genes in the embryonic subventricular zone that predict adult phenotypes. <i>Evf2</i>-regulated <i>Dlx5/6UCE</i>-gene distances and directions (closer to or further from gene targets) can be decoupled from gene target transcriptional effects. <i>Evf2</i> regulates <i>Evf2</i>-ribonucleoprotein (RNP) binding in a combinatorial manner to key regulatory sites, including chr6 <i>Evf2</i>-<i>Dlx5/6UCE</i>-gene guided sites, <i>Evf1/2</i> RNA-directly bound sites (RBSs), and inter-chromosomal HiC looping interactions. RBSs divide chromosomes into multi-megabase domains enriched for <i>Evf2</i>-regulated RNP recruitment, transcription factor motifs, and HiC looping interactions. Together with <i>Evf2</i>-controlled homeobox motif recognition at <i>Evf2</i>-RNP recruitment sites and transcription factor motif enrichment in RBSs with DNA identity, this work supports direct roles for <i>Evf2</i> in enhancer-gene guidance and transcriptional regulation, with the potential for both site-specific and chromosomal domain specific RNP recruitment.</p>

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Single-cell transcriptomics of ventral forebrain progenitors identifies Evf2 enhancer lncRNA-enhancer gene guidance through direct RNA binding and RNP recruitment domains

  • 期刊论文

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  • 发表日期：

    2025年7月26日

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  • Edward Li,
  • Abhijit Chakraborty,
  • Sara J. Kohtz,
  • Ivelisse Cajigas,
  • Laura Hinojosa-Gonzalez,
  • Fion Shiau,
  • Ryan Bertossi,
  • Robert J. Vassar,
  • Jack A. Kessler,
  • Ferhat Ay,
  • Brian S. Clark,
  • Jhumku D. Kohtz

摘要

During mouse embryonic brain development, the Evf2 ultraconserved enhancer (UCE) lncRNA guides the Dlx5/6UCE to ~129 sites across chr6. However, previous work identified only 4 transcriptionally regulated targets associated with Evf2-Dlx5/6UCE-gene guidance, raising questions about the significance of Evf2-regulated Dlx5/6UCE-gene interactions. Here, single-cell transcriptomics reveal far greater alignment between Evf2-Dlx5/6UCE-gene guidance and transcriptional regulation than previously reported. Evf2 divides chr6 into short-range ( <10 Mb distant), activated genes, and long/super-long-range (10-129 Mb distant), repressed genes, identifying seizure regulating genes in the embryonic subventricular zone that predict adult phenotypes. Evf2-regulated Dlx5/6UCE-gene distances and directions (closer to or further from gene targets) can be decoupled from gene target transcriptional effects. Evf2 regulates Evf2-ribonucleoprotein (RNP) binding in a combinatorial manner to key regulatory sites, including chr6 Evf2-Dlx5/6UCE-gene guided sites, Evf1/2 RNA-directly bound sites (RBSs), and inter-chromosomal HiC looping interactions. RBSs divide chromosomes into multi-megabase domains enriched for Evf2-regulated RNP recruitment, transcription factor motifs, and HiC looping interactions. Together with Evf2-controlled homeobox motif recognition at Evf2-RNP recruitment sites and transcription factor motif enrichment in RBSs with DNA identity, this work supports direct roles for Evf2 in enhancer-gene guidance and transcriptional regulation, with the potential for both site-specific and chromosomal domain specific RNP recruitment.