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Updated: Jun 1, 2026
10:25
Real-time Bioluminescence Imaging of Notch Signaling Dynamics during Murine Neurogenesis
Published on: December 12, 2019
A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development.
Peter Mulligan1, Fajun Yang, Luisa Di Stefano
1Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
Molecular Cell
|May 21, 2011
Summary
The study reveals a new SIRT1 corepressor complex involving histone demethylase LSD1. This complex epigenetically represses genes in the Notch signaling pathway, impacting animal development.
Area of Science:
- Epigenetics
- Developmental Biology
- Molecular Biology
Background:
- Histone modifications regulate gene expression during animal development.
- SIRT1 (NAD(+)-dependent deacetylase) removes histone H4K16 acetylation, promoting heterochromatin.
- The role of SIRT1 in euchromatic gene regulation and its interaction with other chromatin modifiers are not fully understood.
Purpose of the Study:
- To investigate the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci.
- To determine if SIRT1 acts with other chromatin-modifying enzymes to control developmental gene expression.
- To characterize the composition and function of a novel SIRT1 corepressor complex.
Main Methods:
- Co-immunoprecipitation to identify interacting proteins.
- Biochemical assays to assess histone deacetylase and demethylase activities.
- Genetic analysis in Drosophila to study developmental phenotypes and pathway interactions.
Main Results:
- A SIRT1 corepressor complex containing histone H3K4 demethylase LSD1/KDM1A was identified.
- SIRT1 and LSD1 directly interact and cooperate in H4K16 deacetylation and H3K4 demethylation.
- This concerted action represses genes involved in the Notch signaling pathway.
- Mutations in Drosophila SIRT1 and LSD1 orthologs caused similar developmental defects and interacted with the Notch pathway.
Conclusions:
- SIRT1 functions within a corepressor complex with LSD1 to epigenetically regulate gene expression.
- This complex plays a conserved role in H4K16 deacetylation and H3K4 demethylation.
- The SIRT1-LSD1 complex is crucial for repressing Notch pathway genes and normal animal development.
- Findings provide new insights into conserved epigenetic mechanisms controlling development.
Related Concept Videos
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
02:24Regulation of Expression Occurs at Multiple Steps
Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
02:24Regulation of Expression Occurs at Multiple Steps
Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
01:23Regulation of Expression at Multiple Steps
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...