10 de setembre de 2018

A three-dimensional and Bioinformatics approach to identify how genes are controlled in differentiating stem cells

Biola M. Javierre has published a paper on her work on cardiomyocytes; cells that form the heart; and the stem cells that originate cardiomyocytes, previous to joining the institute.  We asked her about the significance of this work and how she will apply these techniques to study malignant blood diseases.

In a paper published in Nature Communications in June the authors describe complex mechanisms called PIRs that regulate (switch on and off) genes in the stem cells. They also discovered that the PIRs are reorganized as the stem cells differentiate and develop into heart fibres so that they can specifically regulate cardiac functions.  Finally they showed that the genes that the PIRs regulate are the same ones that have been identified in other genomic studies as the genes associated with heart structure and rhythm of heartbeat.  “It is important to know that the genes and regulating mechanisms are present in the stem cells and functioning when they develop into heart cells, “Javierre tells us. “This is vital for research into reconstruction of hearts using stem cells because regenerated parts of the heart will need to behave like the original parts and beat correctly.”

Although many genes can now be identified, it has become clear that most of them work in interrelated networks making it very hard to find the genes responsible for a particular characteristic.  Additionally, they are often regulated by structures, such as the PIRs, that can be on a very distant part of the strand of DNA; this is possible as the DNA is wound up in extremely complicated shapes like a monstrous ball of tangled wool bringing distant parts into close contact so they can interact.  All this means that finding all the genes and regulating structures that affect a biological process such as heartbeat or cancer is extremely difficult.  “Our work is to measure millions of interactions between genes on different parts of the genome,” says Javierre, “Using statistical and computing techniques we map out these extremely complex connections and this is what we have been able to do for genes affecting structure of the heart and the rhythm of the heartbeat.”

A new “omnigenomic” model of complex disease has been proposed, in which each biological characteristic is controlled by a few “core genes” and many “non-core” genes. Javierre confirms that the recently published work fits with this, “Our complex interacting subnetwork of genes in the cardiomyocytes coincides with genes identified as being involved in heartrate in other types of genomic studies.  We believe the same might be true in pathological biological processes in stem cells such as leukaemia and this is where my research will be directed in the Josep Carreras Leukaemia Institute,” she confirmed.


Original reference

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.

Choy MK, Javierre BM, Williams SG, Baross SL, Liu Y, Wingett SW, Akbarov A, Wallace C, Freire-Pritchett P, Rugg-Gunn PJ, Spivakov M, Fraser P, Keavney BD.

Nat Commun. 2018 Jun 28;9(1):2526. doi: 10.1038/s41467-018-04931-0.  PMID: 29955040

Funding information

The 3D Chromatin Group is supported by and has received funding from the Ramon y Cajal Programme  (RYC-2016-19665), Spanish Ministry of Science, Innovation and University