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X-chromosome inactivation in humans: initiation and imprinting

Grant number: 09/17481-6
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2010
Effective date (End): April 30, 2015
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Lygia da Veiga Pereira
Grantee:Joana Carvalho Moreira de Mello
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Epigenetic phenomena as genomic imprinting and X chromosome inactivation (XCI) have been widely studied in mice. While most of the processes and steps involved in XCI in mice are well studied, in humans our knowledge is still very limited, specially during early embryo development.Advances in single-cell whole transcriptome high throughput sequencing techniques (RNA-Seq) bring a new era to the XCI field. Single-cell RNA-Seq results from 2-cell to the blastocyst stage of human embryos were published by Xue et cols and Yan et cols in 2013. Using bioinformatics techniques we searched for the XIST gene expression level (a gene closely involved in XCI) throughout the human pre-implantation embryo development. We aligned reads generated by RNA-Seq assays to the human reference genome looking for variants in gene transcriptional regions and to identify the origin of the expressed allele. Our results show that XIST expression starts from the 8-cell stage and is stabilized and upregulated at the female blastocyst stage. We also show that the transcriptional silence of X-linked genes started at the blastocyst stage and is independent of parental origin but this does not apply for all genes. We concluded that the completion of the transcriptional silence step is probably established during post-implantation stage. The search for X-linked imprinted genes is challenging due to the XCI phenomenon. Nevertheless, X-imprinted genes were reported in mice. In humans, no X-imprinted genes were found so far, but phenotypic differences reported in Turner's syndrome (45,X) women was related to the parental origin of the X chromosome inherited. This suggests the existence of X-linked imprinted genes, in particular MAOA, MAOB and USP9X seemed good candidates. By sequencing transcript regions containing heterozygous SNPs in these genes we could access their expression pattern. Our results show no sign of imprinting regulation of MAOA, MAOB or USP9X, neither in human brain nor in human term placenta. This does not rule out the possibility that the phenotypic differences observed in Turner's syndrome women could be the consequence of other unknown X-linked imprinted genes. RNA-Seq of different human female tissues is a powerful approach to finally find the genes involved in such phenotypes.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HE, NANNAN; LIM, SHUJING J.; MOREIRA DE MELLO, JOANA C.; NAVARRO, INJERREAU; BIALECKA, MONIKA; SALVATORI, DANIELA C. F.; VAN DER WESTERLAKEN, LUCETTE A. J.; PEREIRA, LYGIA V.; LOPES, SUSANA M. CHUVA DE SOUSA. At Term, XmO and XpO Mouse Placentas Show Differences in Glucose Metabolism in the Trophectoderm-Derived Outer Zone. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 5, . (09/17481-6, 13/08135-2, 15/03610-0)
MOREIRA DE MELLO, JOANA C.; FERNANDES, GUSTAVO R.; VIBRANOVSKI, MARIA D.; PEREIRA, LYGIA V.. Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing. SCIENTIFIC REPORTS, v. 7, . (15/20844-4, 09/17481-6, 13/08135-2, 15/03610-0)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MELLO, Joana Carvalho Moreira de. X-chromosome inactivation in humans: initiation and imprinting. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) São Paulo.

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