Transcriptional regulation of the human pre-implantation embryo
Author: Madissoon, Elo
Date: 2016-01-29
Location: Hörsalen, Novum, Karolinska Institutet, Huddinge
Time: 09.00
Department: Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition
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Thesis (682.0Kb)
Abstract
Millions of couples worldwide have difficulties in conceiving a child. These couples, affected by infertility, suffer from symptoms of stress. The causes of infertility are largely unknown and current available treatment, in vitro fertilization has moderate success rates. The in vitro fertilization covers pre-implantation stage of the human embryo development. Better understanding of the molecular mechanisms in the early development might help to improve the in vitro fertilization methods.
Much of the knowledge on early development has been gained from model organisms: nematode, fruit fly, zebrafish and mouse. Mouse is a commonly used model organism for mammalian pre-implantation development. Global gene expression studies have been performed on mouse and human. Overall, gene expression changes seem to be similar in principle between the organisms. However, the expression of the first transcribed genes in the early development may not be as conserved between species as other genes expressed later in development. Therefore, human pre-implantation development should also be studied on human material for better translation of the results.
Genes with a dynamic expression profile in human pre-implantation development were identified in Paper I. Various criteria such as conservation, expression profile in mouse, relevance in cancer and novelty were applied to choose seventy genes of potential importance in human early development. Expression of those genes was studied in mouse and compared with human orthologues. The results showed differences in the expression profiles between human and mouse.
Paper II found novel regulatory elements and potentially important transcription factors from human early development by single-cell RNA sequencing. About 350 of oocytes and blastomeres from early embryos were studied, the promoters of activated genes were analyzed, and many PRD-like homeodomain genes with first-time evidence of expression were cloned. These genes were suggested to regulate the early development.
Paper III describes the expression pattern, target genes and potential function in early development for the PRD-like homeodomain gene LEUTX. A novel variant of LEUTX was identified and cloned, providing a full homeodomain-containing and functional isoform of the protein. LEUTX was found expressed exclusively in human pre-implantation embryos. The target genes of LEUTX were enriched among the genes activated by human embryo, which strongly indicated regulatory function for LEUTX in the early development.
The other PRD-like homeodomain containing proteins were studied in Paper IV. Expression of those genes was found to be specific for early development. The targets of CPHX1 and DPRX were found to be enriched among the genes activated in the early human embryo. General overlap of the target genes allowed for discussion of their possible functional redundancy.
The thesis offers novel findings for understanding gene expression and regulation in human pre-implantation embryos. The studies identify novel PRD-like homeodomain containing transcription factors that may have a crucial importance in the regulation of gene expression in the human pre-implantation embryos.
Much of the knowledge on early development has been gained from model organisms: nematode, fruit fly, zebrafish and mouse. Mouse is a commonly used model organism for mammalian pre-implantation development. Global gene expression studies have been performed on mouse and human. Overall, gene expression changes seem to be similar in principle between the organisms. However, the expression of the first transcribed genes in the early development may not be as conserved between species as other genes expressed later in development. Therefore, human pre-implantation development should also be studied on human material for better translation of the results.
Genes with a dynamic expression profile in human pre-implantation development were identified in Paper I. Various criteria such as conservation, expression profile in mouse, relevance in cancer and novelty were applied to choose seventy genes of potential importance in human early development. Expression of those genes was studied in mouse and compared with human orthologues. The results showed differences in the expression profiles between human and mouse.
Paper II found novel regulatory elements and potentially important transcription factors from human early development by single-cell RNA sequencing. About 350 of oocytes and blastomeres from early embryos were studied, the promoters of activated genes were analyzed, and many PRD-like homeodomain genes with first-time evidence of expression were cloned. These genes were suggested to regulate the early development.
Paper III describes the expression pattern, target genes and potential function in early development for the PRD-like homeodomain gene LEUTX. A novel variant of LEUTX was identified and cloned, providing a full homeodomain-containing and functional isoform of the protein. LEUTX was found expressed exclusively in human pre-implantation embryos. The target genes of LEUTX were enriched among the genes activated by human embryo, which strongly indicated regulatory function for LEUTX in the early development.
The other PRD-like homeodomain containing proteins were studied in Paper IV. Expression of those genes was found to be specific for early development. The targets of CPHX1 and DPRX were found to be enriched among the genes activated in the early human embryo. General overlap of the target genes allowed for discussion of their possible functional redundancy.
The thesis offers novel findings for understanding gene expression and regulation in human pre-implantation embryos. The studies identify novel PRD-like homeodomain containing transcription factors that may have a crucial importance in the regulation of gene expression in the human pre-implantation embryos.
List of papers:
I. Madissoon E, Töhönen V, Vesterlund L, Katayama S, Unneberg P, Inzunza J, Hovatta O, Kere J. Differences in gene expression between mouse and human for dynamically regulated genes in early embryo. PLoS One 2014 Aug 4;9(8):e102949.
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II. Töhönen V, Katayama S, Vesterlund L, Jouhilahti EM, Sheikhi M, Madissoon E, Filippini-Cattaneo G, Jaconi M, Johnsson A, Bürglin TR, Linnarsson S, Hovatta O, Kere J. Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development. Nature Communications 2015 Sep 11;6:8207.
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III. Jouhilahti E, Madissoon E, Vesterlund L, Töhönen V, Krjutškov K, Reyes AP, Petropoulos S, Månsson R, Linnarsson S, Bürglin TR, Lanner F, Hovatta O, Katayama S, Kere J. The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation. [Submitted]
IV. Madissoon E, Jouhilahti E, Vesterlund L, Töhönen V, Krjutškov K, Petropoulos S, Einarsdottir E, Linnarsson S, Lanner F, Månsson R, Hovatta O, Bürglin TR, Katayama S, Kere J. PRD-like homeodomain transcription factors regulate human Embryo Genome Activation by target gene activation and suppression. [Submitted]
I. Madissoon E, Töhönen V, Vesterlund L, Katayama S, Unneberg P, Inzunza J, Hovatta O, Kere J. Differences in gene expression between mouse and human for dynamically regulated genes in early embryo. PLoS One 2014 Aug 4;9(8):e102949.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Töhönen V, Katayama S, Vesterlund L, Jouhilahti EM, Sheikhi M, Madissoon E, Filippini-Cattaneo G, Jaconi M, Johnsson A, Bürglin TR, Linnarsson S, Hovatta O, Kere J. Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development. Nature Communications 2015 Sep 11;6:8207.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Jouhilahti E, Madissoon E, Vesterlund L, Töhönen V, Krjutškov K, Reyes AP, Petropoulos S, Månsson R, Linnarsson S, Bürglin TR, Lanner F, Hovatta O, Katayama S, Kere J. The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation. [Submitted]
IV. Madissoon E, Jouhilahti E, Vesterlund L, Töhönen V, Krjutškov K, Petropoulos S, Einarsdottir E, Linnarsson S, Lanner F, Månsson R, Hovatta O, Bürglin TR, Katayama S, Kere J. PRD-like homeodomain transcription factors regulate human Embryo Genome Activation by target gene activation and suppression. [Submitted]
Institution: Karolinska Institutet
Supervisor: Kere, Juha
Issue date: 2016-01-07
Rights:
Publication year: 2016
ISBN: 978-91-7676-152-6
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