Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis, Antanas, Xue, Li, Trainor, Cecelia D., Dangeti, Mohan, Gillinder, Kevin, Siatecka, Miroslawa, Nebor, Danitza, Peters, Luanne L., Perkins, Andrew C. and Bieker, James J. (2017) Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development. Development, 144 3: 430-440. doi:10.1242/dev.145656

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Author Planutis, Antanas
Xue, Li
Trainor, Cecelia D.
Dangeti, Mohan
Gillinder, Kevin
Siatecka, Miroslawa
Nebor, Danitza
Peters, Luanne L.
Perkins, Andrew C.
Bieker, James J.
Title Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development
Formatted title
Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development
Journal name Development   Check publisher's open access policy
ISSN 1477-9129
0950-1991
Publication date 2017-01-31
Year available 2017
Sub-type Article (original research)
DOI 10.1242/dev.145656
Open Access Status File (Publisher version)
Volume 144
Issue 3
Start page 430
End page 440
Total pages 11
Place of publication Cambridge, United Kingdom
Publisher The Company of Biologists
Language eng
Subject 1312 Molecular Biology
1309 Developmental Biology
Abstract Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.
Formatted abstract
Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.
Keyword Anemia
Cytokine effects
Erythropoiesis
Monoallelic mutation
Mouse
Transcription factor
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P30 CA034196
R01 DK046865
R01 DK100692
Institutional Status UQ

 
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