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Targeted DamID in C. elegans reveals a direct role for LIN-22 and NHR-25 in antagonizing the epidermal stem cell fate.

ABSTRACT: Transcription factors are key players in gene networks controlling cell fate specification during development. In multicellular organisms, they display complex patterns of expression and binding to their targets, hence, tissue specificity is required in the characterization of transcription factor-target interactions. We introduce here targeted DamID (TaDa) as a method for tissue-specific transcription factor target identification in intact Caenorhabditis elegans animals. We use TaDa to recover targets in the epidermis for two factors, the HES1 homolog LIN-22, and the NR5A1/2 nuclear hormone receptor NHR-25. We demonstrate a direct link between LIN-22 and the Wnt signaling pathway through repression of the Frizzled receptor lin-17. We report a direct role for NHR-25 in promoting cell differentiation via repressing the expression of stem cell-promoting GATA factors. Our results expand our understanding of the epidermal gene network and highlight the potential of TaDa to dissect the architecture of tissue-specific gene regulatory networks.

SUBMITTER: Katsanos D

PROVIDER: S-EPMC8816332 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Targeted DamID in <i>C. elegans</i> reveals a direct role for LIN-22 and NHR-25 in antagonizing the epidermal stem cell fate.

Katsanos Dimitris D Barkoulas Michalis M

Science advances 20220204 5

Transcription factors are key players in gene networks controlling cell fate specification during development. In multicellular organisms, they display complex patterns of expression and binding to their targets, hence, tissue specificity is required in the characterization of transcription factor-target interactions. We introduce here targeted DamID (TaDa) as a method for tissue-specific transcription factor target identification in intact <i>Caenorhabditis elegans</i> animals. We use TaDa to r ...[more]

PMID: 35119932

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Project description:Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

Dataset Information

Targeted DamID in C. elegans reveals a direct role for LIN-22 and NHR-25 in antagonizing the epidermal stem cell fate.

Publications

Targeted DamID in <i>C. elegans</i> reveals a direct role for LIN-22 and NHR-25 in antagonizing the epidermal stem cell fate.

Similar Datasets

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