Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development

An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in...

Full description

Bibliographic Details
Main Authors:	Hasegawa, Yu, Taylor, Deanne, Ovchinnikov, Dmitry A., Wolvetang, Ernst J., de Torrenté, Laurence, Mar, Jessica C.
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546122/

id	pubmed-4546122
recordtype	oai_dc
spelling	pubmed-45461222015-09-01 Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development Hasegawa, Yu Taylor, Deanne Ovchinnikov, Dmitry A. Wolvetang, Ernst J. de Torrenté, Laurence Mar, Jessica C. Research Article An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in the same population. Application of these ideas to the study of early human embryonic development may reveal important insights into the transcriptional programs controlling this process, based on which components are most tightly regulated. Using a published single cell RNA-seq data set of human embryos collected at four-cell, eight-cell, morula and blastocyst stages, we identified genes with the most stable, invariant expression across all four developmental stages. Stably-expressed genes were found to be enriched for those sharing indispensable features, including essentiality, haploinsufficiency, and ubiquitous expression. The stable genes were less likely to be associated with loss-of-function variant genes or human recessive disease genes affected by a DNA copy number variant deletion, suggesting that stable genes have a functional impact on the regulation of some of the basic cellular processes. Genes with low expression variability at early stages of development are involved in regulation of DNA methylation, responses to hypoxia and telomerase activity, whereas by the blastocyst stage, low-variability genes are enriched for metabolic processes as well as telomerase signaling. Based on changes in expression variability, we identified a putative set of gene expression markers of morulae and blastocyst stages. Experimental validation of a blastocyst-expressed variability marker demonstrated that HDDC2 plays a role in the maintenance of pluripotency in human ES and iPS cells. Collectively our analyses identified new regulators involved in human embryonic development that would have otherwise been missed using methods that focus on assessment of the average expression levels; in doing so, we highlight the value of studying expression variability for single cell RNA-seq data. Public Library of Science 2015-08-19 /pmc/articles/PMC4546122/ /pubmed/26288249 http://dx.doi.org/10.1371/journal.pgen.1005428 Text en © 2015 Hasegawa 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hasegawa, Yu Taylor, Deanne Ovchinnikov, Dmitry A. Wolvetang, Ernst J. de Torrenté, Laurence Mar, Jessica C.
spellingShingle	Hasegawa, Yu Taylor, Deanne Ovchinnikov, Dmitry A. Wolvetang, Ernst J. de Torrenté, Laurence Mar, Jessica C. Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
author_facet	Hasegawa, Yu Taylor, Deanne Ovchinnikov, Dmitry A. Wolvetang, Ernst J. de Torrenté, Laurence Mar, Jessica C.
author_sort	Hasegawa, Yu
title	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
title_short	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
title_full	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
title_fullStr	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
title_full_unstemmed	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development
title_sort	variability of gene expression identifies transcriptional regulators of early human embryonic development
description	An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in the same population. Application of these ideas to the study of early human embryonic development may reveal important insights into the transcriptional programs controlling this process, based on which components are most tightly regulated. Using a published single cell RNA-seq data set of human embryos collected at four-cell, eight-cell, morula and blastocyst stages, we identified genes with the most stable, invariant expression across all four developmental stages. Stably-expressed genes were found to be enriched for those sharing indispensable features, including essentiality, haploinsufficiency, and ubiquitous expression. The stable genes were less likely to be associated with loss-of-function variant genes or human recessive disease genes affected by a DNA copy number variant deletion, suggesting that stable genes have a functional impact on the regulation of some of the basic cellular processes. Genes with low expression variability at early stages of development are involved in regulation of DNA methylation, responses to hypoxia and telomerase activity, whereas by the blastocyst stage, low-variability genes are enriched for metabolic processes as well as telomerase signaling. Based on changes in expression variability, we identified a putative set of gene expression markers of morulae and blastocyst stages. Experimental validation of a blastocyst-expressed variability marker demonstrated that HDDC2 plays a role in the maintenance of pluripotency in human ES and iPS cells. Collectively our analyses identified new regulators involved in human embryonic development that would have otherwise been missed using methods that focus on assessment of the average expression levels; in doing so, we highlight the value of studying expression variability for single cell RNA-seq data.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546122/
_version_	1613262532739334144

Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development

Similar Items