Stanley is a graduate student at the Princess Margaret Cancer Centre at the University of Toronto, researching how the non-coding part of the human genome has an impact on cancer development. Follow him on twitter at @StanInScience.
While the concepts of natural selection, heredity and genetics were discovered by the landmark contributions from the likes of Darwin and Mendel in the 1800s and early 1900s, the idea of heredity – understanding how the information of an organism goes from one generation to the next – date back to the ancient great thinkers of Hippocrates, Pythagoras and Aristotle. Considering this simplistic timeline, the double helical structure of DNA – the hereditary material that encodes who we are – discovered by Wilkins, Franklin, Watson and Crick 64 years ago appear relatively recent. The human genome and what it may be about, is thus not a new concept. But where are we now?
Prior to the first sequencing of the human genome in 2001, scientists thought our genome contained <300 000 genes made up of DNA sequences, the genetic units that code for proteins and are passed down through generations. It turned out that only ~1.5% of the entire diploid human genome (two sets of chromosome – from mom and dad) encode for only ~20 000 protein-coding genes. It was later found that alterations in these genes can drive disease development. Many, many groups continue to work persistently to unveil the function of these genes in normal and disease biology.
To truly appreciate the vastness of the human genome, we need to understand the existence of the other 98.5% of noncoding DNA sequences. Once considered “junk DNA”, the noncoding genome contains various elements. The functional elements we know to-date are known as cis-regulatory elements. These elements can be nearby (i.e promoters) or far away (i.e enhancers) from their recognised target gene(s), and when they are bound by specific factors, these elements can form loops in three-dimensional space within the nucleus (Figure) to regulate the expression of these target gene(s). Intriguingly, mutations mapping to these cis-regulatory elements can cause changes like those observed in the actual mutations in target genes. It turns out that the binding of these specific factors cannot bind normally, ultimately affecting the activity of these regulatory elements.
(Figure adapted from Zhou et al., Cancer Discovery, 2016)
Ultimately, the essence of epigenomics is to question the three-dimensional genome, as opposed to thinking of DNA as a linear object. Every cell nucleus contains an almost identical sequence, yet it is the epigenome that plays major roles in giving rise to different tissue types. Specifically, this two-meter long DNA sequence within every cell incredibly wraps around histone proteins (nucleosomes – DNA packaging) in beads-on-a-string structure (chromatin). Because of this structure, the chromatin structure in any given tissue type can be rather dynamic. The nucleosomes can be very close together resulting in a relatively “closed” heterochromatin conformation, or be in a relatively “open” euchromatin conformation. It is these added features on top of the naked DNA sequence that allow for genome shape and the binding of specific factors to account for genes to be expressed differently.
Hence, the noncoding genome has become a dominant focus of many laboratories and global consortia with the vision to characterize the functional elements in the entire human genome across various tissue types. Using modern molecular biology techniques in combination with sequencing, we are now capable of mapping these “open” and “closed” areas, locating where specific factors bind and depict chromatin loop interactions (loops) at a single-cell level in various cell and tissue types.
Conceptualizing heredity, proving that heredity exists through experimental evidence, solving the physical structure of DNA, the sequencing the whole human genome, and now able to profile the chromatin landscape of a given tissue type at a single cell level – how far we have come. With this new knowledge, we can infer and demonstrate the impact of genetic and epigenetic errors within the noncoding genome to ultimately use that knowledge to treat diseases.
Further reading:
No comments:
Post a Comment