The ability to culture stem cells in vitro has provided access to a wide variety of cellular states that are inaccessible or too rare to study otherwise. Here we demonstrate the use of stem cells to model two distinct developmental transitions, and examine the role that epigenetic regulation of transcription plays in controlling stem cell fate and function.
First, we examine the transition from mouse embryonic stem cells (mESCs), representative of the pre-implantation epiblast, to mouse epiblast stem cells (mEpiSCs), representative of the post-implantation epiblast. These two states, while maintained by distinct signaling pathways, both retain the ability to re-integrate into their respective tissue of origin and contribute to the development of the entire organism. While the transcriptome of the two cell types is largely similar, they rely on dramatically different sets of enhancers to regulate that expression. 97% of the genes that are shared between the two states undergo a change in enhancer usage in the transition. The enhancers that arise in the mEpiSC state are present, but inactive, in the preceding mESC state and become enhancer clusters downstream in development.
Second, we examine the development of oligodendrocytes from oligodendrocyte progenitors (OPCs). Oligodendrocytes wrap neural axons in a lipid-rich sheath known as myelin. This myelin is required for proper signal conduction, but is subject to immune attack in multiple sclerosis (MS). OPCs replace damaged oligodendrocytes early in the course of disease, but eventually fail. A chemical genetics screen reveals that BET bromodomain proteins are required for oligodendrocyte development. These proteins are epigenetic readers that integrate chromatin state and other signals to allow transcription elongation at many genes. Other inhibitors of elongation show similar effects on development, and treatment with BET bromodomain inhibitor (S)-JQ1 blocks activation of oligodendrocyte genes. Elongation genes are enriched at MS risk alleles, and these alleles show evidence of enhancer function. In MS tissue, elongation genes are disrupted, and Hexim1 is increased in oligodendrocyte lineage cells.
In combination, our results demonstrate the broad role that the epigenetic regulation of transcription plays in modulating cellular identity and function in stem cells, both in development and disease.