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The Long Non-Coding RNA MALAT1 Modulates NR4A1 Expression through a Downstream Regulatory Element in Specific Cancer

Sara Wernig-Zorc1,2, Uwe Schwartz3, Paulina Martínez-Rodríguez4

  • 1Regensburg Center for Biochemistry [RCB], Universität Regensburg, 93053 Regensburg, Germany.

International Journal of Molecular Sciences
|May 25, 2024
PubMed

Insights

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) long non-coding RNA fine-tunes NR4A1 gene expression by altering regulatory element accessibility. This mechanism is cell-type specific, observed in breast cancer but not pancreatic cancer.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Long non-coding RNAs (lncRNAs) regulate gene expression and are implicated in cancer.
  • Limited understanding exists regarding lncRNA effects on gene regulatory elements (REs).

Purpose of the Study:

  • To investigate how the MALAT1 lncRNA influences gene expression via regulatory elements.
  • To elucidate the MALAT1/NR4A1 regulatory axis.

Main Methods:

  • Time-resolved MALAT1 knockdown followed by parallel RNA-seq and ATAC-seq.
  • CRISPR interference (CRISPR-i) assays.
  • Analysis of The Cancer Genome Atlas (TCGA) data.
  • Experimental validation in breast and pancreatic cancer cell lines.

Main Results:

  • MALAT1 knockdown decreased accessibility downstream of the NR4A1 gene, correlating with reduced NR4A1 expression.
  • A functional MALAT1/NR4A1 axis was identified, involving an NR4A1-downstream RE.
  • A positive correlation between NR4A1 expression and RE accessibility was found in breast cancer, but not pancreatic cancer.

Conclusions:

  • MALAT1 fine-tunes NR4A1 expression by modulating the accessibility of a downstream RE.
  • This regulatory mechanism is cell type-specific, validated in breast cancer cells (MCF7) but not pancreatic cancer cells (PANC1).
Keywords:
MALAT1NR4A1breast cancerchromatin accessibilitychromatin-associated lncRNAs

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