Noncanonical inheritance of phenotypic information by protein amyloids

All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known...

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Published in:	Nature cell biology Vol. 26; no. 10; pp. 1712 - 1724
Main Authors:	Eroglu, Matthew, Zocher, Tanner, McAuley, Jacob, Webster, Rachel, Xiao, Maggie Z. X., Yu, Bin, Mok, Calvin, Derry, W. Brent
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2024 Nature Publishing Group
Subjects:	101/28 13/89 14/19 14/35 38/91 45/70 631/136 631/136/2434 631/208/176 631/80 631/80/474/2085 64/11 82/29 82/58 82/80 82/83 96/34 Amyloid - metabolism Animals Biomedical and Life Sciences Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Cancer Research Cell Biology Cell differentiation Developmental Biology Drug therapy Epigenesis, Genetic Epigenetics Female Genetic analysis Germ Cells - drug effects Germ Cells - metabolism Heredity Histones Inheritance Patterns - genetics Life Sciences Male Nucleic acids Offspring Pattern formation Phenotype Phenotypes Proteasome 26S Proteasome Endopeptidase Complex - genetics Proteasome Endopeptidase Complex - metabolism Proteasomes Proteins Proteomics Proteomics - methods Sex differentiation Sex Differentiation - genetics Stem Cells
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Summary:	All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness. Eroglu et al. describe protein amyloid structures that are stably inherited across generations and transmit epigenetic memory in Caenorhabditis elegans . MSTR protein loss results in a transgenerational feminization phenotype through ectopic GLD-1 expression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-024-01494-9