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Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage
The basic helix-loop-helix (bHLH) transcription factor ASCL2 plays essential roles in diploid multipotent trophoblast progenitors, intestinal stem cells, follicular T-helper cells, as well as during epidermal development and myogenesis. During early development, Ascl2 expression is regulated by geno...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105033/ https://www.ncbi.nlm.nih.gov/pubmed/30096149 http://dx.doi.org/10.1371/journal.pgen.1007587 |
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author | Bogutz, Aaron B. Oh-McGinnis, Rosemary Jacob, Karen J. Ho-Lau, Rita Gu, Ting Gertsenstein, Marina Nagy, Andras Lefebvre, Louis |
author_facet | Bogutz, Aaron B. Oh-McGinnis, Rosemary Jacob, Karen J. Ho-Lau, Rita Gu, Ting Gertsenstein, Marina Nagy, Andras Lefebvre, Louis |
author_sort | Bogutz, Aaron B. |
collection | PubMed |
description | The basic helix-loop-helix (bHLH) transcription factor ASCL2 plays essential roles in diploid multipotent trophoblast progenitors, intestinal stem cells, follicular T-helper cells, as well as during epidermal development and myogenesis. During early development, Ascl2 expression is regulated by genomic imprinting and only the maternally inherited allele is transcriptionally active in trophoblast. The paternal allele-specific silencing of Ascl2 requires expression of the long non-coding RNA Kcnq1ot1 in cis and the deposition of repressive histone marks. Here we show that Del(7AI), a 280-kb deletion allele neighboring Ascl2, interferes with this process in cis and leads to a partial loss of silencing at Ascl2. Genetic rescue experiments show that the low level of Ascl2 expression from the paternal Del(7AI) allele can rescue the embryonic lethality associated with maternally inherited Ascl2 mutations, in a level-dependent manner. Despite their ability to support development to term, the rescued placentae have a pronounced phenotype characterized by severe hypoplasia of the junctional zone, expansion of the parietal trophoblast giant cell layer, and complete absence of invasive glycogen trophoblast cells. Transcriptome analysis of ectoplacental cones at E7.5 and differentiation assays of Ascl2 mutant trophoblast stem cells show that ASCL2 is required for the emergence or early maintenance of glycogen trophoblast cells during development. Our work identifies a new cis-acting mutation interfering with Kcnq1ot1 silencing function and establishes a novel critical developmental role for the transcription factor ASCL2. |
format | Online Article Text |
id | pubmed-6105033 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61050332018-08-30 Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage Bogutz, Aaron B. Oh-McGinnis, Rosemary Jacob, Karen J. Ho-Lau, Rita Gu, Ting Gertsenstein, Marina Nagy, Andras Lefebvre, Louis PLoS Genet Research Article The basic helix-loop-helix (bHLH) transcription factor ASCL2 plays essential roles in diploid multipotent trophoblast progenitors, intestinal stem cells, follicular T-helper cells, as well as during epidermal development and myogenesis. During early development, Ascl2 expression is regulated by genomic imprinting and only the maternally inherited allele is transcriptionally active in trophoblast. The paternal allele-specific silencing of Ascl2 requires expression of the long non-coding RNA Kcnq1ot1 in cis and the deposition of repressive histone marks. Here we show that Del(7AI), a 280-kb deletion allele neighboring Ascl2, interferes with this process in cis and leads to a partial loss of silencing at Ascl2. Genetic rescue experiments show that the low level of Ascl2 expression from the paternal Del(7AI) allele can rescue the embryonic lethality associated with maternally inherited Ascl2 mutations, in a level-dependent manner. Despite their ability to support development to term, the rescued placentae have a pronounced phenotype characterized by severe hypoplasia of the junctional zone, expansion of the parietal trophoblast giant cell layer, and complete absence of invasive glycogen trophoblast cells. Transcriptome analysis of ectoplacental cones at E7.5 and differentiation assays of Ascl2 mutant trophoblast stem cells show that ASCL2 is required for the emergence or early maintenance of glycogen trophoblast cells during development. Our work identifies a new cis-acting mutation interfering with Kcnq1ot1 silencing function and establishes a novel critical developmental role for the transcription factor ASCL2. Public Library of Science 2018-08-10 /pmc/articles/PMC6105033/ /pubmed/30096149 http://dx.doi.org/10.1371/journal.pgen.1007587 Text en © 2018 Bogutz et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Bogutz, Aaron B. Oh-McGinnis, Rosemary Jacob, Karen J. Ho-Lau, Rita Gu, Ting Gertsenstein, Marina Nagy, Andras Lefebvre, Louis Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title | Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title_full | Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title_fullStr | Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title_full_unstemmed | Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title_short | Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage |
title_sort | transcription factor ascl2 is required for development of the glycogen trophoblast cell lineage |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105033/ https://www.ncbi.nlm.nih.gov/pubmed/30096149 http://dx.doi.org/10.1371/journal.pgen.1007587 |
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