How Do Female Cells Inactivate One X Chromosome?

Hendrik Marks Ph.D Group leader Epigenetics of Stem Cells Radboud University, Department of Molecular Biology, RIMLS, Nijmegen, The Netherlands

MedicalResearch.com Interview with:
Hendrik Marks Ph.D
Group leader Epigenetics of Stem Cells
Radboud University, Department of Molecular Biology, RIMLS
Nijmegen, The Netherlands

Medical Research: What is the background for this study? What are the main findings?

Dr. Marks: In mammals, sex is determined by two so-called “sex” chromosome: males have a single X chromosome as well as a Y chromosome, whereas females have two copies of the X chromosome. However, if both X chromosomes were to be active in female cells, these cells would have a double dosis of X-chromosomal gene products as compared to male cells. As this is lethal for almost all cells, female cells shut off one X chromosome in every cell in a process called X inactivation. This process occurs during early embryonic development.

A lot is known about how this process is turned on, but is was unclear how such a silencing process spreads along a full chromosome. In order to further study this, we used female mouse embryonic stem cells (mESCs) as a model system and initiated X inactivation by means of differentiation. With the latest technologies, we were able to keep the two X chromosomes apart and measure one of them – with its 166 million base pairs (Mbs) – in detail. Every day we checked which parts of the chromosome had been switched off. The whole process took about eight days, and the inactivation spreads out from the centre of the X chromosome towards the ends. That doesn’t happen gradually but moves jumpwise from domain to domain. Domains are long pieces of DNA (of around 1Mb) that cluster together in knots. As it seems that X inactivation jumps from domain to domain, we now know that these domains are co-regulated. Also, we collected strong evidence that the same process is occurring in human.

Medical Research: What should clinicians and patients take away from your report?

Dr. Marks: Our study is very fundamental in nature. It shows how a full chromosome gets silenced, and it also points towards a very important role of the recently-discovered domains it this process. However, It is not unlikely that some diseases that are linked to the X chromosome in female, the so-called X linked diseases, are due to improper spreading across domains. Thus, in some of these diseases it might turn out very helpful investigating the domain structure of the X chromosomes, and/or SNPs that present at the borders of the domains.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Marks: After one of the X chromosomes has been inactivated, it will stay inactive forever. It would be very interesting to discover why sometimes the one while in other cases the other X chromosome is inactivated during development. That could help in treating X-linked diseases – like Rett syndrome and fragile X syndrome in females. Reactivating (part of) the ‘right’ X chromosome could be a potential treatment for these diseases. So one of the next steps that the field is aiming at is to figure out how to do that, and our current studies provide new clues for potential strategies.

Citation:

‘Dynamics of gene silencing during X inactivation using allele-specific RNA-seq’

Hendrik Marks, Hindrik H. D. Kerstens, Tahsin Stefan Barakat, Erik Splinter, René A. M. Dirks, Guido van Mierlo, Onkar Joshi, Shuang-Yin Wang, Tomas Babak, Cornelis A. Albers, Tüzer Kalkan, Austin Smith, Alice Jouneau, Wouter de Laat, Joost Gribnau and Hendrik G. Stunnenberg

Genome Biology; doi:10.1186/s13059-015-0698-x

 

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