EHMT2 suppresses the variation of transcriptional switches in the mouse embryo

EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–...

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Autores principales:	Tie-Bo Zeng, Nicholas Pierce, Ji Liao, Purnima Singh, Kin Lau, Wanding Zhou, Piroska E. Szabó
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/07cfe93f4d4c429a8647ea0c1b891960
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spelling	oai:doaj.org-article:07cfe93f4d4c429a8647ea0c1b8919602021-11-25T05:53:03ZEHMT2 suppresses the variation of transcriptional switches in the mouse embryo1553-73901553-7404https://doaj.org/article/07cfe93f4d4c429a8647ea0c1b8919602021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601470/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification. Author summary Developmental variation is the property of normal development, and its regulation is poorly understood. Variable developmental delay is found in embryos that carry mutations of epigenetic modifiers, suggesting a role of chromatin in controlling developmental delay and its variable nature. We analyzed a genetic series of mutations and found that EHMT2 suppresses variation of developmental delay and also suppresses the variation of transcriptional switches at the transition between gastrulation and organ specification.Tie-Bo ZengNicholas PierceJi LiaoPurnima SinghKin LauWanding ZhouPiroska E. SzabóPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Tie-Bo Zeng Nicholas Pierce Ji Liao Purnima Singh Kin Lau Wanding Zhou Piroska E. Szabó EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
description	EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification. Author summary Developmental variation is the property of normal development, and its regulation is poorly understood. Variable developmental delay is found in embryos that carry mutations of epigenetic modifiers, suggesting a role of chromatin in controlling developmental delay and its variable nature. We analyzed a genetic series of mutations and found that EHMT2 suppresses variation of developmental delay and also suppresses the variation of transcriptional switches at the transition between gastrulation and organ specification.
format	article
author	Tie-Bo Zeng Nicholas Pierce Ji Liao Purnima Singh Kin Lau Wanding Zhou Piroska E. Szabó
author_facet	Tie-Bo Zeng Nicholas Pierce Ji Liao Purnima Singh Kin Lau Wanding Zhou Piroska E. Szabó
author_sort	Tie-Bo Zeng
title	EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
title_short	EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
title_full	EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
title_fullStr	EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
title_full_unstemmed	EHMT2 suppresses the variation of transcriptional switches in the mouse embryo
title_sort	ehmt2 suppresses the variation of transcriptional switches in the mouse embryo
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/07cfe93f4d4c429a8647ea0c1b891960
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EHMT2 suppresses the variation of transcriptional switches in the mouse embryo

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