The blueprint for human life lies within the DNA in the nucleus of each of our cells. In human cells, around six and a half feet of this genetic material must be condensed to fit inside the nucleus. DNA condensation is not random. To function properly, the genetic material is highly organized into loop structures that often bring together widely separated sections of the genome critical to the regulation of gene activity. "A carefully orchestrated regulatory machinery is required to ensure every cell in the body is expressing its correct gene set to exert its dedicated function," said the study's first author Daniel Bsteh. In the study, Bsteh and his colleagues specifically examined developmental genes that are repressed by molecules known as Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2).

 

Through a genetic screen conducted in mouse embryonic stem cells, the scientists identified a protein, PDS5A, that modifies loops without affecting histone modifications. This enabled Bsteh and colleagues to specifically study the effects of loops and 3D genome organization on gene silencing. The loss of PDS5A disrupted the loops -- and therefore the long-range interactions between repressed developmental genes. Further, looping genes together maintains the silent state. When PRC1- and PRC2-repressed genes are physically separated, eliminating the loops, normally silent genes become activated in aberrant ways. PDS5A is a subunit of a larger protein complex called cohesin, which is the master regulator of 3D genome organization.

 

"Cohesin mutations are known to drive several human diseases, including developmental disorders and cancer. What's striking about our discovery is that it reveals a dependence of PRC 1 and PRC 2 activity on the precise regulation of 3D genome organization by cohesin, suggesting that 'cohesinopathies' may be linked to aberrant developmental gene silencing." Support for this research came from the Austrian Academy of Sciences, the New Frontiers Group of the Austrian Academy of Sciences (grant NFG-05), the Human Frontiers Science Program Career Development Award (CDA00036/2014-C), and startup funding from the USC Norris Comprehensive Cancer Center.