MiR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor

Justin J. Cassidy; Aashish R. Jha; Diana M. Posadas; Ritika Giri; Koen J.T. Venken; Jingran Ji; Hongmei Jiang; Hugo J. Bellen; Kevin P. White; Richard W. Carthew

doi:10.1016/j.cell.2013.10.057

MiR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor

Justin J. Cassidy, Aashish R. Jha, Diana M. Posadas, Ritika Giri, Koen J.T. Venken, Jingran Ji, Hongmei Jiang, Hugo J. Bellen, Kevin P. White, Richard W. Carthew^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

Abstract

Gene expression has to withstand stochastic, environmental, and genomic perturbations. For example, in the latter case, 0.5%-1% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks and, ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole-genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibits these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.

Original language	English (US)
Pages (from-to)	1556-1567
Number of pages	12
Journal	Cell
Volume	155
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2013.10.057
State	Published - Dec 19 2013

Funding

We thank the following for reagents: F.B. Gao, J. Reinitz, the Bloomington Stock Center, the Developmental Hybridoma Studies Bank, and NCI Frederick. Thanks to C. LaBonne for comments on the manuscript. We also thank Bionimbus ( http://www.bionimbus.org ). We acknowledge support from the Chicago Biomedical Consortium (to J.J.C.), the Malkin and Rappaport Foundations (to J.J.C.), the Pew Latin American Fellows Program (to D.M.P.), the McNair Medical Institute (to K.J.T.V.), the Howard Hughes Medical Institute (to K.J.T.V. and H.J.B.), and the NIH for grants T32GM008061 (to J.J.C.), T32 HL094282 (to A.R.J.), P50 GM81892 (to K.P.W.), T32 GM007526 (to K.J.T.V.), and GM068743 and GM077581 (to R.W.C.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2013.10.057

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@article{3665b810b25442ae89cbc043031e6e23,

title = "MiR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor",

abstract = "Gene expression has to withstand stochastic, environmental, and genomic perturbations. For example, in the latter case, 0.5\%-1\% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks and, ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole-genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibits these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.",

author = "Cassidy, \{Justin J.\} and Jha, \{Aashish R.\} and Posadas, \{Diana M.\} and Ritika Giri and Venken, \{Koen J.T.\} and Jingran Ji and Hongmei Jiang and Bellen, \{Hugo J.\} and White, \{Kevin P.\} and Carthew, \{Richard W.\}",

note = "Funding Information: We thank the following for reagents: F.B. Gao, J. Reinitz, the Bloomington Stock Center, the Developmental Hybridoma Studies Bank, and NCI Frederick. Thanks to C. LaBonne for comments on the manuscript. We also thank Bionimbus ( http://www.bionimbus.org ). We acknowledge support from the Chicago Biomedical Consortium (to J.J.C.), the Malkin and Rappaport Foundations (to J.J.C.), the Pew Latin American Fellows Program (to D.M.P.), the McNair Medical Institute (to K.J.T.V.), the Howard Hughes Medical Institute (to K.J.T.V. and H.J.B.), and the NIH for grants T32GM008061 (to J.J.C.), T32 HL094282 (to A.R.J.), P50 GM81892 (to K.P.W.), T32 GM007526 (to K.J.T.V.), and GM068743 and GM077581 (to R.W.C.). ",

year = "2013",

month = dec,

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doi = "10.1016/j.cell.2013.10.057",

language = "English (US)",

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journal = "Cell",

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AU - Cassidy, Justin J.

AU - Jha, Aashish R.

AU - Posadas, Diana M.

AU - Giri, Ritika

AU - Venken, Koen J.T.

AU - Ji, Jingran

AU - Jiang, Hongmei

AU - Bellen, Hugo J.

AU - White, Kevin P.

AU - Carthew, Richard W.

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PY - 2013/12/19

Y1 - 2013/12/19

N2 - Gene expression has to withstand stochastic, environmental, and genomic perturbations. For example, in the latter case, 0.5%-1% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks and, ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole-genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibits these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.

AB - Gene expression has to withstand stochastic, environmental, and genomic perturbations. For example, in the latter case, 0.5%-1% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks and, ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole-genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibits these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.

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JO - Cell

JF - Cell

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ER -

MiR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor

Abstract

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ASJC Scopus subject areas

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