DNA is found in the nucleus of every cell, woven around proteins called histones. This complex of DNA and proteins found inside the nucleus is called chromatin. In the past, I dedicated a couple of posts to chromatin rearrangements, how they are used by the cell to silence certain genes, and how epigenetic reprogramming has to happen in order for cells to differentiate during development. I'm still learning how these epigenetic mechanisms work, and today I'd like to share with you a couple new readings I've done on the topic.
Chromatin complexes that repress transcription during development are formed by a group of proteins called the Polycomb group (PcG). The proteins in this group form two classes, PRC1 and PRC2. From Wikipedia:
"PRC2 is required for initial targeting of genomic region (PRC Response Elements or PRE) to be silenced, while PRC1 is required for stabilizing this silencing and underlies cellular memory of silenced region after cellular differentiation."In other words, PCR2 recognizes the current chromatin state and targets the regions to be silenced in order to maintain the same state after cell division. This guarantees that an undifferentiated cell like an embryonic stem cell for example, stays undifferentiated for as long as it's needed.
How does PCR2 distinguish active chromatin (activated genes) from the inactivated one (silenced genes)?
Histones are not static. Imagine these molecules undergoing rearrangements every time they need to change the way they interact with DNA. These changes are called histone modifications and are classified based on the type of histone, amino acid, and position at which they undergo the change. Different histone modifications mark different states of the gene. For example, active genes are usually marked by H3K4me3 and H3K36me2/3, whereas inactive genes are marked by H3K27me3.
In , Yuan et al. suggest that active genes are not silenced by PRC2 because, besides having the "active" marks, the chromatin region that contains them is also less compact, with a lower density of nucleosomes and histones H1.
"Once active transcription has ceased upon transcription factor dissociation, either the chromatin-remodeling events or the incorporation of additional histones (including linker histones) would lead to higher nucleosome density, higher H1 content, and more compact chromatin structure, which in turn would convert these nucleosomes from their inert status to ideal substrates of PRC2. Thus, H3K27me3 could be established and lead to further repression of the target genes."To test their hypothesis, Yuan et al. used a mouse model and the gene CYP26a1 as target, and observed that changes in the local density ("compaction") of the chromatin preceded the establishment of silencing marks.
 Wen Yuan, Tong Wu, Hang Fu, Chao Dai, Hui Wu, Nan Liu, Xiang Li, Mo Xu, Zhuqiang Zhang, Tianhui Niu, Zhifu Han, Jijie Chai, Xianghong Jasmine Zhou, Shaorong Gao, & Bing Zhu2 (2012). Dense Chromatin Activates Polycomb Repressive Complex 2 to Regulate H3 Lysine 27 Methylation Science DOI: 10.1126/science.1225237