Role Reversal: Are Transcription Factors Responsible for Heterochromatin Formation?
Regions of eukaryotic chromosomes are classified into two distinct groups: euchromatin, which is generally less compacted and contains actively transcribed genes, and heterochromatin, which is typically more compacted and contains silent genes and the majority of the repeated DNA elements. Transcription factors are generally thought of as proteins that are responsible for stimulating gene transcription in euchromatic regions of chromosomes. However, a recent report from the laboratory of Thomas Jenuwein redefines the role of transcription factors in gene expression and provides evidence that in addition to promoting gene expression, transcription factors can also play important roles in heterochromatin formation and stability.
While regions of heterochromatin are generally thought to contain only silent genes, they are not actually transcriptionally inert. For example, non-coding RNA molecules are transcribed from repeated DNA sequences in pericentromeric heterochromatin in many organisms. The authors expanded on this observation by investigating the relationship between transcription factors and the formation of heterochromatin in mice. They focused on the transcription factor Pax3 because it was previously shown to interact with other heterochromatin-associated proteins. The authors demonstrated that Pax3 localizes to pericentromeric heterochromatin and also binds directly to the major satellite repeat DNA sequences that are present in pericentromeric regions. Furthermore, Pax3 seems to repress transcription from pericentromeric regions, likely by recruiting heterochromatic histone modifications such as trimethylation on histone H3 lysine 9 (H3K9me3). Depletion or mutation of Pax3 results in a decrease in pericentromeric heterochromatin, and was accompanied by an increase in transcription of non-coding RNAs from these regions (heterochromatin and transcription from other regions were not affected).
The authors primarily focused on the role of Pax3 in regulating pericentromeric heterochromatin, but also proposed a model in which transcription factors play a general role in establishment of heterochromatic regions across the genome. This model was supported by their observation that many regions of heterochromatin are enriched for transcription factor binding motifs. The authors raise an intriguing question: what really distinguishes euchromatin from heterochromatin? What do you think? Does chromatin state control transcription, or does transcription control the chromatin state?
Bulut-Karslioglu A. et al. (2012) A transcription factor-based mechanism for mouse heterochromatin formation. Nat Struct Mol Biol. 2012 Sep 16. doi: 10.1038/nsmb.2382. (published online September 16, 2012)