Epigenetic control during embryogenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

To uncover the molecular function of the LSH protein, the Epigenetics group employed a cellular model. In this model cells embryonic stem cells were engineered in such a way that LSH could be tethered to a specific genomic location upon the addition of a specific chemical to the cell culture. This allowed to study the chromatin changes occurring after recruitment of LSH to this specific genomic site. By conducting a systemic analysis of chromatin ingredients, they discovered that LSH was changing the content of a histone variant. Histones are the main components of chromatin and exist in four different 'flavors' with a few variants or subtypes. They found that LSH role is to exchange the histone H2A with the histone variant macroH2A at specific locations in the genome. The incorporation of macroH2A into chromatin gives chromatin specific characteristics: chromatin becomes more compact, has less access to DNA and leads to gene repression of repetitive elements. They also demonstrated that mutations of LSH occurring in ICF4 patients were unable to deposit macroH2A into the genome and were impaired of gene repression. By identifying LSH as part of the machinery that is critical for depositing macroH2A in the genome and thus influencing chromatin composition, they have identified an important molecular pathway that contributes to the complex pathophysiology of the ICF4 syndrome.