Investigation into sexual dimorphisms in autosomal gene expression due to sex chromosome complement effects rather than phenotypic sex
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
Most differences between the sexes have been attributed to hormonal differences. We have recently shown that this is not always the case and that gene activity differences between males and females can be independent of sex itself and instead come about because of differences in the sex chromosomes. Normally females have two X chromosomes and males an X and a Y chromosome. By studying 'sex reversal' where males have two X chromsomes and females an X and a Y chromosome we found many differences between males and females that are not caused by sex itself but rather by the sex chromosomes.
This proposal will explore how this additional layer in the regulation of differences between the sexes works. We will explore the possibility that there are specific genes on the X chromosome which cause these differences by acting as switches to turn on or off many other genes that are not on the X and Y chromosome. Another possibility is that one of the X-chromosomes, the one that is shut-down in every cell in females (to balance with males who have only one X chromosome) sequesters important regulatory factors thereby reducing their availabilty in females. Such a sequestration mechanism could lead to many genes being regulated differently in females. We can test this idea by introducing the mechanism that normally shuts down the X chromosome to another chromosomes and looking for the sex differences in males that we previously found only in females. Understanding the mechanism whereby sex differences come about is important for understanding how strong sex bias arises in many diseases, and will give further insight into the underlying mechanisms and hence open up new therapeutic avenues in the future.
This proposal will explore how this additional layer in the regulation of differences between the sexes works. We will explore the possibility that there are specific genes on the X chromosome which cause these differences by acting as switches to turn on or off many other genes that are not on the X and Y chromosome. Another possibility is that one of the X-chromosomes, the one that is shut-down in every cell in females (to balance with males who have only one X chromosome) sequesters important regulatory factors thereby reducing their availabilty in females. Such a sequestration mechanism could lead to many genes being regulated differently in females. We can test this idea by introducing the mechanism that normally shuts down the X chromosome to another chromosomes and looking for the sex differences in males that we previously found only in females. Understanding the mechanism whereby sex differences come about is important for understanding how strong sex bias arises in many diseases, and will give further insight into the underlying mechanisms and hence open up new therapeutic avenues in the future.
Technical Summary
Differences between males and females are normally attributed to developmental and hormonal differences between the sexes. We have recently demonstrated differences between males and females in gene silencing using a heterochromatin-sensitive reporter gene in vivo. Using 'sex-reversal' mouse models with varying sex chromosome complements, we found that this differential gene silencing was determined by X chromosome dosage, rather than sex. Genome-wide transcription profiling showed that the expression of hundreds of autosomal genes was also sensitive to sex chromosome complement. These genome-wide analyses also uncovered a novel role for Sry in modulating autosomal gene expression in a sex chromosome complement-specific manner. The identification of this additional layer in the establishment of sexual differences has important implications for understanding sexual dimorphisms in physiology and disease. This proposal will employ transgenic tools combined with high-throughput sequencing and bioinformatic analyses to unravel the molecular basis for this novel system. We will investigate the hypotheses that the sex chromosome effect on heterochromatin silencing and autosomal gene expression is due to: 1) the inactive X chromosome acting as a sink for heterochromatin factors and 2) overexpression of genes that escape X chromosome inactivation. Moreover, we have found significant enrichment within the subset of sex chromosome sensitive genes for genes that are also sensitive to the dosage of a key component of heterochromatin, HP1. These genes cluster in regions along the chromosome and bioinformatic analysis indicates that particular repetitive sequence motifs are enriched in their vicinity. We will investigate whether these genes are 'responders' to the sex-chromosome complement effect and whether the mechanism of response involves classical features of heterochromatin nucleated by repetitive sequences.
Planned Impact
Understanding the molecular basis for sexual dimorphisms during T cell development has the potential to impact on a large number of diseases with unexplained sexual dimorphism. Many autoimmune diseases which are thought to be due to the selection of autoreactive T cells show a strong sex bias, insight into the regulatory mechanisms underlying these differences might not only uncover gene expression patterns conferring increased disease susceptibility but also potentially lead to novel interventions. In the shorter term, the information provided might be expected to allow the identification of individuals at risk of particular diseases and identify biomarkers of disease susceptibility. Understanding the molecular mechanisms underlying epigenetic gene silencing will impact on many aspects of the biology of multicellular organisms where cellular identity is achieved by preventing aberrant gene expression. This project has widespread implications for understanding how cells maintain their identity. Clearly such mechanisms are especially crucial for regulating the ability of cells to respond to signals and differentiate as well as preventing cancers that are due to aberrant expression of oncogenes as well the maintenance of the pluripotent state. The latter is crucial in understanding the nature of stem-cells which have potential high impact in the treatment of a large number of degenerative diseases. The lab is located within the Insitute of Clinical Sciences at Imperial College whose mission is to drive the translation of innovative research towards improved health and clinical outcomes. There is a particular strength in epigenetic research providing an ideal combination of access to the relevant technology and intellectual environment to maximise the potential impact of this programme.
Organisations
- Imperial College London (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Francis Crick Institute (Collaboration)
- ETH Zurich (Collaboration)
- University of California, Los Angeles (UCLA) (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
People |
ORCID iD |
Richard Festenstein (Principal Investigator) |
Publications
Festenstein R
(2012)
Context is everything: activators can also repress.
in Nature structural & molecular biology
Yandim Cihangir
(2012)
Heterochromatin effects in Friedreich's ataxia and sexual dimorphism
Description | Rutherford Innovation Fellowship |
Amount | £250,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2017 |
End | 11/2019 |
Description | AA |
Organisation | University of California, Los Angeles (UCLA) |
Department | Department of Integrative Biology and Physiology (formerly the Department of Physiological Science) |
Country | United States |
Sector | Academic/University |
PI Contribution | provision of research material |
Collaborator Contribution | analysis of research material |
Impact | Collaboration between our epigenetics lab and AA who has endocrinology expertise |
Start Year | 2012 |
Description | AW |
Organisation | ETH Zurich |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | We will test his modifier transgenic model on its ability to modify sex chromosome complement effects on gene expression |
Collaborator Contribution | AW will provide transgenic line which will be crossed to CD2 transgenics showing sex dimorphism in heterochromatin-meditated silencing |
Impact | Both work on different aspects of epigenetics. |
Start Year | 2013 |
Description | JG |
Organisation | Imperial College London |
Department | MRC London Institute of Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have discovered potential sex-dimorphism in the regulation of cellular proliferation which is regulated by a heterochromatin component. The collaboration is allowing us to determine whether these gene expression changes result in an altered pronesity to senescence. |
Collaborator Contribution | JG has all the necessary prtocols set up to examine the senscent phenotype in detail and is haring expertise |
Impact | These studies are in progress. |
Start Year | 2016 |
Description | JT |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration with JT allows examination of the contribution of genes on the Y chromosome to sexually dimorphic autosomal gene expression |
Collaborator Contribution | Obtaining genetically altered mice to analyse for effects on sexually dimorphic gene expression is enabling the molecular dissection of how in early deveelopment heterochromatin components have a dimorphic effect. |
Impact | Work in progress |
Start Year | 2016 |
Description | PB |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Crossing of hCD2 variegating lines to the four core genotypes model and analysis of gene expression |
Collaborator Contribution | Provision of specialised murine lines |
Impact | Revealed autosomal genes that are sensitive to sex chromosome complement rather than gender, publications in preparation. |
Start Year | 2008 |
Description | X-inactivation |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaborating on the hypothesis that the inactive X-chromosome might be attracting heterochromatin proteins and thereby regulating sexually dimorphic gene expression |
Collaborator Contribution | We have discovered a hitherto hidden layer in the regulation of sexual dimorphism in gene expression at the epigenetic level. We are using a model system developed by our collaborator to gain insight into the molecular mechanism |
Impact | The research is in progress with no direct outcomes yet. |
Start Year | 2017 |
Description | Debate_MRC Centenary_Future of Science and Medicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | About 60 people attended a live chaired debate followed by questions discussing the impact of science and society on the future of medicine. This was a stimulating discussion which enabled dissection of the promise of basic science in greatly improving health in the future. The attached video will be posted on the MRC CSC website. |
Year(s) Of Engagement Activity | 2013 |
URL | http://vimeo.com/71258144 |
Description | Epigenesys Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at European Network to present novel results showing that a key component of heterochromatin is essential for sex differences very early on in development |
Year(s) Of Engagement Activity | 2016 |
Description | Epigenomics of Common Diseases Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of the finding that a major epigenetic regulator is crucial for regulating sexual differences before sex hormones kick in. |
Year(s) Of Engagement Activity | 2016 |
URL | http://conf.hinxton.wellcome.ac.uk/advancedcourses/ECD2016Programme.pdf |
Description | Presentation at Gordon Conference in Chromatin Structure and Function |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Forum for experts in the field of chromatin and gene regulation to exchange unpublished data in order to further excellence in Science. This is a competitive leading conference in the field. |
Year(s) Of Engagement Activity | 2016 |
Description | Public Symposium on Sexual Dimorphism and Disease |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | International scientists conducting a meeting open to the public fosters public understanding of science Set up collaborations and dialogue with experts in the field of sexual dimorphism and disease |
Year(s) Of Engagement Activity | 2011 |
URL | http://www.college-de-france.fr/site/en-jean-louis-mandel/symposium-2011-11-23.htm |
Description | Webinar Friedreich's ataxia research alliancce |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Supporters |
Results and Impact | Feedback following publication of Lancet paper on epigenetic therapy for Friedreich's ataxia |
Year(s) Of Engagement Activity | 2014 |