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Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues

Transcription factor 4 (TCF4) belongs to the class I basic helix–loop–helix family of transcription factors (also known as E-proteins) and is vital for the development of the nervous system. Aberrations in the TCF4 gene are associated with several neurocognitive disorders such as schizophrenia, inte...

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Autores principales: Sirp, Alex, Shubina, Anastassia, Tuvikene, Jürgen, Tamberg, Laura, Kiir, Carl Sander, Kranich, Laura, Timmusk, Tõnis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9666405/
https://www.ncbi.nlm.nih.gov/pubmed/36407762
http://dx.doi.org/10.3389/fnmol.2022.1033224
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author Sirp, Alex
Shubina, Anastassia
Tuvikene, Jürgen
Tamberg, Laura
Kiir, Carl Sander
Kranich, Laura
Timmusk, Tõnis
author_facet Sirp, Alex
Shubina, Anastassia
Tuvikene, Jürgen
Tamberg, Laura
Kiir, Carl Sander
Kranich, Laura
Timmusk, Tõnis
author_sort Sirp, Alex
collection PubMed
description Transcription factor 4 (TCF4) belongs to the class I basic helix–loop–helix family of transcription factors (also known as E-proteins) and is vital for the development of the nervous system. Aberrations in the TCF4 gene are associated with several neurocognitive disorders such as schizophrenia, intellectual disability, post-traumatic stress disorder, depression, and Pitt-Hopkins Syndrome, a rare but severe autism spectrum disorder. Expression of the human TCF4 gene can produce at least 18 N-terminally distinct protein isoforms, which activate transcription with different activities and thus may vary in their function during development. We used long-read RNA-sequencing and western blot analysis combined with the analysis of publicly available short-read RNA-sequencing data to describe both the mRNA and protein expression of the many distinct TCF4 isoforms in rodent and human neural and nonneural tissues. We show that TCF4 mRNA and protein expression is much higher in the rodent brain compared to nonneural tissues. TCF4 protein expression is highest in the rodent cerebral cortex and hippocampus, where expression peaks around birth, and in the rodent cerebellum, where expression peaks about a week after birth. In human, highest TCF4 expression levels were seen in the developing brain, although some nonneural tissues displayed comparable expression levels to adult brain. In addition, we show for the first time that out of the many possible TCF4 isoforms, the main TCF4 isoforms expressed in the rodent and human brain and other tissues are TCF4-B, -C, -D, -A, and-I. Taken together, our isoform specific analysis of TCF4 expression in different tissues could be used for the generation of gene therapy applications for patients with TCF4-associated diseases.
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spelling pubmed-96664052022-11-17 Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues Sirp, Alex Shubina, Anastassia Tuvikene, Jürgen Tamberg, Laura Kiir, Carl Sander Kranich, Laura Timmusk, Tõnis Front Mol Neurosci Molecular Neuroscience Transcription factor 4 (TCF4) belongs to the class I basic helix–loop–helix family of transcription factors (also known as E-proteins) and is vital for the development of the nervous system. Aberrations in the TCF4 gene are associated with several neurocognitive disorders such as schizophrenia, intellectual disability, post-traumatic stress disorder, depression, and Pitt-Hopkins Syndrome, a rare but severe autism spectrum disorder. Expression of the human TCF4 gene can produce at least 18 N-terminally distinct protein isoforms, which activate transcription with different activities and thus may vary in their function during development. We used long-read RNA-sequencing and western blot analysis combined with the analysis of publicly available short-read RNA-sequencing data to describe both the mRNA and protein expression of the many distinct TCF4 isoforms in rodent and human neural and nonneural tissues. We show that TCF4 mRNA and protein expression is much higher in the rodent brain compared to nonneural tissues. TCF4 protein expression is highest in the rodent cerebral cortex and hippocampus, where expression peaks around birth, and in the rodent cerebellum, where expression peaks about a week after birth. In human, highest TCF4 expression levels were seen in the developing brain, although some nonneural tissues displayed comparable expression levels to adult brain. In addition, we show for the first time that out of the many possible TCF4 isoforms, the main TCF4 isoforms expressed in the rodent and human brain and other tissues are TCF4-B, -C, -D, -A, and-I. Taken together, our isoform specific analysis of TCF4 expression in different tissues could be used for the generation of gene therapy applications for patients with TCF4-associated diseases. Frontiers Media S.A. 2022-11-02 /pmc/articles/PMC9666405/ /pubmed/36407762 http://dx.doi.org/10.3389/fnmol.2022.1033224 Text en Copyright © 2022 Sirp, Shubina, Tuvikene, Tamberg, Kiir, Kranich and Timmusk. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Sirp, Alex
Shubina, Anastassia
Tuvikene, Jürgen
Tamberg, Laura
Kiir, Carl Sander
Kranich, Laura
Timmusk, Tõnis
Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title_full Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title_fullStr Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title_full_unstemmed Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title_short Expression of alternative transcription factor 4 mRNAs and protein isoforms in the developing and adult rodent and human tissues
title_sort expression of alternative transcription factor 4 mrnas and protein isoforms in the developing and adult rodent and human tissues
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9666405/
https://www.ncbi.nlm.nih.gov/pubmed/36407762
http://dx.doi.org/10.3389/fnmol.2022.1033224
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