The National Cancer Institute (NCI) Symposium on Chromosome Biology: Epigenetics in Development sponsored by the NCI Center for Cancer Research and the Center of Excellence in Chromosome Biology was a great success. The two days of talks covered the role of chromatin modifications in development and disease and the interplay between epigenetics, non-coding RNAs, transcriptional regulation, and transgenerational inheritance.
Histone Levels, Nucleosomes, and Aging
Dr. Jessica Tyler opened the morning session of the first day by letting us know what lies ahead as we age. In budding yeast, her group has found that total histone levels decrease by 70%. Interestingly, nucleosome levels are down 60% across the genome, but the positioning of nucleosomes is maintained. This reduction in nucleosome density correlated with an induction of expression of all yeast genes. The take home message, if you want to stay young you need to keep your histones!
Myc: Universally Amped
c-Myc protein has been implicated in many physiological or pathological processes via regulation of numerous target genes, but a unifying principle of Myc action has remained elusive. Dr. David Levens generated a mouse line that fuses endogenous Myc to enhanced green fluorescent protein to examine Myc function in primary lymphocytes and embryonic stem cells. In so doing, his group discovered that Myc is not an on-off specifier of gene activity but is a universal amplifier of gene expression increasing output at all active promoters. This principle may begin to explain some of the curious features of Myc Biology.
miRNAs in Neuronal Diversity
The nervous system appears bilaterally symmetric structurally, but brains are functionally asymmetric! Dr. Olivier Hobert described the establishment of the nervous system functional asymmetry during early developmental stages in C. elegans. His group has shown that this mechanism relies on a temporally separated two step activation of the lsy-6 miRNA, programming the precursor for the left neuron to become “left”. This outstanding study constitutes a wonderful example of early developmental stages programming of cells to execute a specific fate later in development and add a stone in the wall of our understanding of neuronal diversity.
Chromatin Modifying Enzymes in iPSC Reprogramming
Dr. George Daley from Children’s Hospital Boston discussed the role of chromatin modifying enzymes in iPSC reprogramming. Through the use of shRNA mediated knockdowns and small molecule inhibitors, his laboratory has shown that while the activity of PRC1 and PRC2 is essential for reprogramming, DOT1L inhibition enhanced reprogramming. Inhibition of DOT1L, a H3K79 specific methyltranferase, resulted in increased expression of Nanog and Lin28 genes which play an essential role in cellular reprogramming. The work demonstrated possible uses of chromatin modifying enzymes in enhancing the efficiency of reprogramming.
A Little Less Methyltransferase Can Go a Long Way
Chromatin changes related to aging are not limited to just nucleosome density. Dr. Anne Brunet’s group identified in C. elegans that, similar to the reduction of H3K4me3 levels induced by caloric restriction, a reduction in the expression of H3K4 methyltransferases increased longevity. Together these data link excess levels of H3K4me3 to aging. Most intriguing, transgenerational inheritance of lifespan extension appears specific for the H3K4 methylation regulators. A deficiency in chromatin regulators in the parental generation is able to affect wild type descendants for up to 5 generations suggesting that there is an incomplete reprogramming of chromatin modifications in C. elegans.
Regulatory Potential in Repeats
One-half to two-thirds of the human genome is derived from repetitive sequences that can be classified as transposable elements! Using a transchromosomic mouse strain that transmits most of the human chromosome 21 via the female germline, Dr. Duncan Odon described the latent regulatory potential of the repetitive human genome. His group showed that heterologous regulatory environment can transcriptionally activate transposon derived human regulatory regions by inducing changes in DNA methylation and chromatin state.
RNAi Picks Up Where DNA Methylation Leaves Off
Dr. Scott Kennedy from University of Wisconsin-Madison discussed heritability of RNAi in C elegans. Kennedy’s group identified Heritable RNAi Defective 1 (Hrde1) gene that codes for Argonaute protein. In germ cells, Hrde1 interacts with nuclear RNAi factors to establish H3K9 methylation marks. In species lacking DNA methylation such as C elegans, a dedicated RNAi machinery may play an important role in epigenetic inheritance.
**EpiGenie would like to give a big electronic chest bump to our conference coverage trifecta for this event including: Drs. Marc Bailly, Becky Brose, and Satyajeet Khare who brought you these highlights.