Phase separation as a possible mechanism for dosage sensitivity.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
15 Jan 2024
15 Jan 2024
Historique:
received:
04
04
2023
accepted:
27
11
2023
medline:
16
1
2024
pubmed:
16
1
2024
entrez:
15
1
2024
Statut:
epublish
Résumé
Deletion of haploinsufficient genes or duplication of triplosensitive ones results in phenotypic effects in a concentration-dependent manner, and the mechanisms underlying these dosage-sensitive effects remain elusive. Phase separation drives functional compartmentalization of biomolecules in a concentration-dependent manner as well, which suggests a potential link between these two processes, and warrants further systematic investigation. Here we provide bioinformatic and experimental evidence to show a close link between phase separation and dosage sensitivity. We first demonstrate that haploinsufficient or triplosensitive gene products exhibit a higher tendency to undergo phase separation. Assessing the well-established dosage-sensitive genes HNRNPK, PAX6, and PQBP1 with experiments, we show that these proteins undergo phase separation. Critically, pathogenic variations in dosage-sensitive genes disturb the phase separation process either through reduced protein levels, or loss of phase-separation-prone regions. Analysis of multi-omics data further demonstrates that loss-of-function genetic perturbations on phase-separating genes cause similar dysfunction phenotypes as dosage-sensitive gene perturbations. In addition, dosage-sensitive scores derived from population genetics data predict phase-separating proteins with much better performance than available sequence-based predictors, further illustrating close ties between these two parameters. Together, our study shows that phase separation is functionally linked to dosage sensitivity and provides novel insights for phase-separating protein prediction from the perspective of population genetics data.
Sections du résumé
BACKGROUND
BACKGROUND
Deletion of haploinsufficient genes or duplication of triplosensitive ones results in phenotypic effects in a concentration-dependent manner, and the mechanisms underlying these dosage-sensitive effects remain elusive. Phase separation drives functional compartmentalization of biomolecules in a concentration-dependent manner as well, which suggests a potential link between these two processes, and warrants further systematic investigation.
RESULTS
RESULTS
Here we provide bioinformatic and experimental evidence to show a close link between phase separation and dosage sensitivity. We first demonstrate that haploinsufficient or triplosensitive gene products exhibit a higher tendency to undergo phase separation. Assessing the well-established dosage-sensitive genes HNRNPK, PAX6, and PQBP1 with experiments, we show that these proteins undergo phase separation. Critically, pathogenic variations in dosage-sensitive genes disturb the phase separation process either through reduced protein levels, or loss of phase-separation-prone regions. Analysis of multi-omics data further demonstrates that loss-of-function genetic perturbations on phase-separating genes cause similar dysfunction phenotypes as dosage-sensitive gene perturbations. In addition, dosage-sensitive scores derived from population genetics data predict phase-separating proteins with much better performance than available sequence-based predictors, further illustrating close ties between these two parameters.
CONCLUSIONS
CONCLUSIONS
Together, our study shows that phase separation is functionally linked to dosage sensitivity and provides novel insights for phase-separating protein prediction from the perspective of population genetics data.
Identifiants
pubmed: 38225666
doi: 10.1186/s13059-023-03128-z
pii: 10.1186/s13059-023-03128-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
17Subventions
Organisme : Key Technologies Research and Development Program
ID : 2021YFF1200900
Organisme : Key Technologies Research and Development Program
ID : 2018YFA0507504
Organisme : National Natural Science Foundation of China
ID : 32070666
Organisme : National Natural Science Foundation of China
ID : 32170684
Organisme : National Science and Technology Innovation 2030
ID : 2022ZD0213900
Organisme : National Science and Technology Innovation 2030
ID : 2022ZD0204900
Informations de copyright
© 2024. The Author(s).
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