Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish
4 affiliations
- 1Department of Cell Biology, Duke University, Durham, North Carolina, United States of America
- 2Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America
- 3UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- 4Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
Abstract
Lysosome-rich enterocytes (LREs) are a specialized population of intestinal cells that mediate the uptake and absorption of dietary proteins in fish and neonatal mammals. Loss of LRE function causes inhibited growth and poor survival due to protein malnutrition. Previously, we reported that in zebrafish loss of Plasmolipin (pllp), an endosomal membrane protein highly expressed in LREs, impairs LRE differentiation and dietary protein absorption, resulting in marked reduction in survival rates. Raising pllp homozygous mutants surviving to adulthood and in-crossing them for multiple generations resulted in a recovery of survival and growth, even when fed a low protein diet. To uncover mechanisms underlying this phenomenon, we compared the older adapted pllp allele with genetically related wild type (WT) fish and a newly generated pllp mutant allele. Using transcriptome profiling and quantitative protein absorption assays, we found that the adapted pllp mutants exhibit upregulation of LRE endocytic components associated with a capacity for protein absorption that exceeds that of WT. This hyperactivation of LRE endocytic and absorptive activity is accompanied by transcriptional regulation of immune genes that may contribute to the enhanced survival of pllp mutants in the face of increased exposure to environmental antigens. Genetic analyses indicate that these divergent phenotypes emerge gradually over generations and can recur in an independently generated pllp allele upon inbreeding and natural selection. Overall, our study illustrates that genome-wide transcriptional changes are associated with stable improvements in intestinal function and organismal survival in response to protein malnutrition. Author summary: In this study, we investigated how zebrafish adapt to protein malnutrition when the function of specialized intestinal protein-absorbing enterocytes, also found in newborn mammals, is impaired. We observed that fish carrying a mutation that severely disrupts intestinal protein absorption gradually recovered their ability to survive over multiple generations of inbreeding, even though the underlying mutation remained intact. By comparing gene activity in these adapted fish with that of newly generated mutants, we found that the adapted state is associated with changes in two systems: enterocytes show increased protein uptake and degradation that even surpass those of wild type fish, while the immune system was simultaneously recalibrated to dampen inflammation. We further show that this trajectory can be recapitulated in a second, independently generated mutant line that underwent a strikingly similar recovery trajectory over successive generations. Together, our findings reveal that animals can overcome a severe, heritable nutritional deficit through a gradual, genome-wide transcriptional response that fundamentally reshapes intestinal function across generations.
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BibTeX
@article{wang2026genome,
title = {{Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish}},
author = {Siyao Wang and Laura Childers and Fernando Martinez III and Michel Bagnat and Jieun Park},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012071},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012071},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish
AU - Siyao Wang
AU - Laura Childers
AU - Fernando Martinez III
AU - Michel Bagnat
AU - Jieun Park
PY - 2026
DA - 2026/09/28
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012071
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012071
AB - Lysosome-rich enterocytes (LREs) are a specialized population of intestinal cells that mediate the uptake and absorption of dietary proteins in fish and neonatal mammals. Loss of LRE function causes inhibited growth and poor survival due to protein malnutrition. Previously, we reported that in zebrafish loss of Plasmolipin (pllp), an endosomal membrane protein highly expressed in LREs, impairs LRE differentiation and dietary protein absorption, resulting in marked reduction in survival rates. Raising pllp homozygous mutants surviving to adulthood and in-crossing them for multiple generations resulted in a recovery of survival and growth, even when fed a low protein diet. To uncover mechanisms underlying this phenomenon, we compared the older adapted pllp allele with genetically related wild type (WT) fish and a newly generated pllp mutant allele. Using transcriptome profiling and quantitative protein absorption assays, we found that the adapted pllp mutants exhibit upregulation of LRE endocytic components associated with a capacity for protein absorption that exceeds that of WT. This hyperactivation of LRE endocytic and absorptive activity is accompanied by transcriptional regulation of immune genes that may contribute to the enhanced survival of pllp mutants in the face of increased exposure to environmental antigens. Genetic analyses indicate that these divergent phenotypes emerge gradually over generations and can recur in an independently generated pllp allele upon inbreeding and natural selection. Overall, our study illustrates that genome-wide transcriptional changes are associated with stable improvements in intestinal function and organismal survival in response to protein malnutrition. Author summary: In this study, we investigated how zebrafish adapt to protein malnutrition when the function of specialized intestinal protein-absorbing enterocytes, also found in newborn mammals, is impaired. We observed that fish carrying a mutation that severely disrupts intestinal protein absorption gradually recovered their ability to survive over multiple generations of inbreeding, even though the underlying mutation remained intact. By comparing gene activity in these adapted fish with that of newly generated mutants, we found that the adapted state is associated with changes in two systems: enterocytes show increased protein uptake and degradation that even surpass those of wild type fish, while the immune system was simultaneously recalibrated to dampen inflammation. We further show that this trajectory can be recapitulated in a second, independently generated mutant line that underwent a strikingly similar recovery trajectory over successive generations. Together, our findings reveal that animals can overcome a severe, heritable nutritional deficit through a gradual, genome-wide transcriptional response that fundamentally reshapes intestinal function across generations.
SN - 1553-7404
ER -