The genes that are responsible for maintaining each cell type form DNA loops that link control elements for these genes. This surprising genome structure is generated and reinforced by two essential protein complexes that bridge the loops and contribute to proper gene regulation.
The DNA loop structure is essential for regulating the activity of cell-type-specific genes and thus maintaining cell state. Deficiencies in the protein complexes that help form and reinforce these DNA loops can cause multiple syndromes and diseases, including Opitz-Kaveggia syndrome, Lujan syndrome, schizophrenia, and Cornelia de Lange syndrome.
A team of researchers from Whitehead Institute, MIT, University of Colorado, and University of Massachusetts have discovered that each cell type in our bodies has a unique genome structure, which is due to a newly discovered mechanism that controls our genes. The protein complexes that generate this genome structure play a pivotal role in regulating gene transcription and cell state, and have been implicated in multiple developmental diseases.
"I think we have a fundamental new insight into the underlying causes of several neurological and developmental diseases, including Opitz-Kaveggia syndrome, Lujan syndrome and Cornelia de Lange syndrome," says Whitehead Institute Member Richard Young. "And it comes with a surprising new understanding of the control of genes."
According to the Young lab's paper, published online in Nature this week, a DNA loop formed at the beginning of cell-type-specific genes enables activation of these genes. Each cell type, such as skin cells, nerve cells, or embryonic stem cells, has its own gene expression program to maintain its cell state. For gene activation, regulatory factors and gene expression machinery, bound to two different parts of the DNA called the promoter and the enhancer, must come in contact. This contact, which is facilitated and maintained by protein complexes called Mediator and Cohesin, forms a set of DNA loops that is specific to each cell type.
"That's such a surprise," says Young, whose lab is deciphering the overall cellular circuitry required to regulate gene expression and cell state. "We thought that a loop of DNA probably formed at the beginning of some genes-it's an old model-but we didn't expect that loops are formed by these complexes at active cell-type-specific genes."
Problems with this DNA loop structure can interfere with the activation of cell-type-specific genes, which can cause the cell to lose its normal state. Indeed, mutations in Mediator and Cohesin, the protein complexes that contribute to DNA loop formation, at cell-type-specific genes, can cause various developmental syndromes and diseases.