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Identification of the Imprinted KLF14 Transcription Factor Undergoing Human-Specific Accelerated Evolution

Authors :
Hiroyuki Sasaki
Philippe Arnaud
Stephen W. Scherer
Andrew R. Carson
Charles Lee
Keiko Kobayashi
George H. Perry
Sayeda Abu-Amero
Kazuhiko Nakabayashi
Robert Feil
Layla Parker-Katiraee
Masahiro Kaneda
Anne C. Stone
Gudrun E. Moore
Makiko Meguro-Horike
Takahiro Yamada
Program in Genetics and Genomic Biology
Hospital for Sick Children-University of Toronto McLaughlin Centre
Génétique, Reproduction et Développement (GReD)
Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Institut de Génétique Moléculaire de Montpellier (IGMM)
Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Fetal Growth and Developmental Group
University College of London [London] (UCL)
Division of Epigenomics and Development
Kyushu University [Fukuoka]
Department of Maternal-Fetal Biology
National Research Institute for Child Health and Development
University of Toronto
Source :
PLoS Genetics, PLoS Genetics, Public Library of Science, 2007, 3 (5), pp.e65. ⟨10.1371/journal.pgen.0030065⟩, PLoS Genetics, Vol 3, Iss 5, p e65 (2007)
Publication Year :
2007
Publisher :
HAL CCSD, 2007.

Abstract

Imprinted genes are expressed in a parent-of-origin manner and are located in clusters throughout the genome. Aberrations in the expression of imprinted genes on human Chromosome 7 have been suggested to play a role in the etiologies of Russell-Silver Syndrome and autism. We describe the imprinting of KLF14, an intronless member of the Krüppel-like family of transcription factors located at Chromosome 7q32. We show that it has monoallelic maternal expression in all embryonic and extra-embryonic tissues studied, in both human and mouse. We examine epigenetic modifications in the KLF14 CpG island in both species and find this region to be hypomethylated. In addition, we perform chromatin immunoprecipitation and find that the murine Klf14 CpG island lacks allele-specific histone modifications. Despite the absence of these defining features, our analysis of Klf14 in offspring from DNA methyltransferase 3a conditional knockout mice reveals that the gene's expression is dependent upon a maternally methylated region. Due to the intronless nature of Klf14 and its homology to Klf16, we suggest that the gene is an ancient retrotransposed copy of Klf16. By sequence analysis of numerous species, we place the timing of this event after the divergence of Marsupialia, yet prior to the divergence of the Xenarthra superclade. We identify a large number of sequence variants in KLF14 and, using several measures of diversity, we determine that there is greater variability in the human lineage with a significantly increased number of nonsynonymous changes, suggesting human-specific accelerated evolution. Thus, KLF14 may be the first example of an imprinted transcript undergoing accelerated evolution in the human lineage.<br />Author Summary Imprinted genes are expressed in a parent-of-origin manner, where one of the two inherited copies of the imprinted gene is silenced. Aberrations in the expression of these genes, which generally regulate growth, are associated with various developmental disorders, emphasizing the importance of their discovery and analysis. In this study, we identify a novel imprinted gene, named KLF14, on human Chromosome 7. It is predicted to bind DNA and regulate transcription and was shown to be expressed from the maternally inherited chromosome in all human and mouse tissues examined. Surprisingly, we did not identify molecular signatures generally associated with imprinted regions, such as DNA methylation. Additionally, the identification of numerous DNA sequence variants led to an in-depth analysis of the gene's evolution. It was determined that there is greater variability in KLF14 in the human lineage, when compared to other primates, with a significantly increased number of polymorphisms encoding for changes at the protein level, suggesting human-specific accelerated evolution. As the first example of an imprinted transcript undergoing accelerated evolution in the human lineage, we propose that the accumulation of polymorphisms in KLF14 may be aided by the silencing of the inactive allele, allowing for stronger selection.

Subjects

Subjects :
Cancer Research
MESH: Sequence Analysis, DNA
MESH: Selection, Genetic
Extraembryonic Membranes
030204 cardiovascular system & hematology
DNA Methyltransferase 3A
Histones
Mice
0302 clinical medicine
MESH: DNA Methylation
Conditional gene knockout
MESH: Gene Expression Regulation, Developmental
MESH: Animals
MESH: Proteins
MESH: Syndrome
DNA (Cytosine-5-)-Methyltransferases
MESH: Genetic Variation
MESH: CpG Islands
Genetics (clinical)
MESH: Evolution, Molecular
Genetics
Mammals
Sp Transcription Factors
MESH: Histones
0303 health sciences
Gene Expression Regulation, Developmental
MESH: Synteny
[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN]
Syndrome
CpG site
DNA methylation
MESH: Kruppel-Like Transcription Factors
Research Article
MESH: DNA (Cytosine-5-)-Methyltransferases
MESH: Abnormalities, Multiple
lcsh:QH426-470
MESH: Sp Transcription Factors
Molecular Sequence Data
Kruppel-Like Transcription Factors
MESH: Autistic Disorder
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
Synteny
Evolution, Molecular
Genomic Imprinting
03 medical and health sciences
Species Specificity
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Animals
Humans
MESH: Species Specificity
Abnormalities, Multiple
Epigenetics
RNA, Messenger
Autistic Disorder
Selection, Genetic
Gene
Molecular Biology
MESH: Mice
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
MESH: RNA, Messenger
Evolutionary Biology
MESH: Humans
MESH: Molecular Sequence Data
Human evolutionary genetics
MESH: Extraembryonic Membranes
Genetic Variation
Proteins
Genetics and Genomics
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Sequence Analysis, DNA
DNA Methylation
MESH: Genomic Imprinting
lcsh:Genetics
CpG Islands
Genomic imprinting
Chromatin immunoprecipitation
030217 neurology & neurosurgery

Details

Language :
English
ISSN :
15537390 and 15537404
Database :
OpenAIRE
Journal :
PLoS Genetics, PLoS Genetics, Public Library of Science, 2007, 3 (5), pp.e65. ⟨10.1371/journal.pgen.0030065⟩, PLoS Genetics, Vol 3, Iss 5, p e65 (2007)
Accession number :
edsair.doi.dedup.....ae99439832d00dc594603179e21e1baa