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More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment.

ABSTRACT: The molecular mechanisms governing normal neurodevelopment are tightly regulated by the action of transcription factors. Repressor element 1 (RE1) silencing transcription factor (REST) is widely documented as a regulator of neurogenesis that acts by recruiting corepressor proteins and repressing neuronal gene expression in non-neuronal cells. The REST corepressor 1 (CoREST1), CoREST2, and CoREST3 are best described for their role as part of the REST complex. However, recent evidence has shown the proteins have the ability to repress expression of distinct target genes in a REST-independent manner. These findings indicate that each CoREST paralogue may have distinct and critical roles in regulating neurodevelopment and are more than simply "REST corepressors," whereby they act as independent repressors orchestrating biological processes during neurodevelopment.

SUBMITTER: Maksour S

PROVIDER: S-EPMC7070449 | biostudies-literature | 2020 Mar/Apr

REPOSITORIES: biostudies-literature

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More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment.

Maksour Simon S Ooi Lezanne L Dottori Mirella M

eNeuro 20200310 2

The molecular mechanisms governing normal neurodevelopment are tightly regulated by the action of transcription factors. Repressor element 1 (RE1) silencing transcription factor (REST) is widely documented as a regulator of neurogenesis that acts by recruiting corepressor proteins and repressing neuronal gene expression in non-neuronal cells. The REST corepressor 1 (CoREST1), CoREST2, and CoREST3 are best described for their role as part of the REST complex. However, recent evidence has shown th ...[more]

PMID: 32075869

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Project description:BackgroundChromatin-modifying proteins are key players in the regulation of development and cell differentiation in animals. Most chromatin modifiers, however, predate the evolution of animal multicellularity, and how they gained new functions and became integrated into the regulatory networks underlying development is unclear. One way this may occur is the evolution of new scaffolding proteins that integrate multiple chromatin regulators into larger complexes that facilitate coordinated deposition or removal of different chromatin modifications. We test this hypothesis by analyzing the evolution of the CoREST-Lsd1-HDAC complex.ResultsUsing phylogenetic analyses, we show that a bona fide CoREST homolog is found only in choanoflagellates and animals. We then use the sea anemone Nematostella vectensis as a model for early branching metazoans and identify a conserved CoREST complex by immunoprecipitation and mass spectrometry of an endogenously tagged Lsd1 allele. In addition to CoREST, Lsd1 and HDAC1/2 this complex contains homologs of HMG20A/B and PHF21A, two subunits that have previously only been identified in mammalian CoREST complexes. NvCoREST expression overlaps fully with that of NvLsd1 throughout development, with higher levels in differentiated neural cells. NvCoREST mutants, generated using CRISPR-Cas9, fail to develop beyond the primary polyp stage, thereby revealing essential roles during development and for the differentiation of cnidocytes that phenocopy NvLsd1 mutants. We also show that this requirement is cell autonomous using a cell-type-specific rescue approach.ConclusionsThe identification of a Nematostella CoREST-Lsd1-HDAC1/2 complex, its similarity in composition with the vertebrate complex, and the near-identical expression patterns and mutant phenotypes of NvCoREST and NvLsd1 suggest that the complex was present before the last common cnidarian-bilaterian ancestor and thus represents an ancient component of the animal developmental toolkit.

Dataset Information

More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment.

Publications

More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment.

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