A scanning electron micrograph of a human blastocyst (5 days after fertilization of the egg), revealing the inner cell mass that will become the embryo. Image courtesy of Yorgos Nikas, Wellcome Images
Life. Bits. Self.
The development of human life is an indisputable marvel of choreographed complexity: A single fertilized egg divides and multiplies, the resulting cells differentiating into the roughly 300 cell types required to build a human being.
Among the great and enduring questions of developmental biology is how exactly embryogenesis occurs. What process or plan directs differentiating cells to do what they do, to choose their pathways to becoming neurons, fat cells, hair cells or various hormone secreting cells?
In a paper published today in Cell, a multi-institutional team of scientists, including Bing Ren, PhD, head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego and professor in the UCSD School of Medicine’s Department of Cellular and Cellular Medicine, describe how genes are turned on and off to direct early human development – and report novel genetic mechanisms that play key roles not just in normal development but perhaps in diseases like cancer as well.
Using large-scale genomics technologies, the researchers focused on two key processes in unprecedented detail. The first involves the tacking of methyl molecules to cytosine, one of the four DNA bases that comprise the genetic code; the second involves chemical modifications to proteins called histones, which provide the scaffolding used by winding DNA in cell nuclei.
Histone modification, the researchers found, is more commonly used to regulate genes in early embryonic development, switching them on and off as needed. “DNA methylation” tends to be used in the later stages of development when cells are increasingly locked into specific fates and functions.
“You can sort of glean the logic of animal development in this difference,” said Ren in a news release issued by the Ludwig Institute. “Histone methylation is relatively easy to reverse. But reversing DNA methylation is a complex process, one that requires more resources and is much more likely to result in potentially deleterious mutations.
“So it makes sense that histone methylation is largely used to silence master genes that may be needed at multiple points during development, while DNA methylation is mostly used to switch off genes at later stages, when cells have already been tailored to specific functions, and those genes are less likely to be needed again.”
The scientists also noted two other significant findings:
- The human genome is pocked with more than 1,200 regions kept consistently free of DNA methylation throughout development. Many master regulator genes reside in these regions, dubbed “DNA methylation valleys.” Interestingly, these regions were found to be abnormally methylated in colon cancer tissues.
- The identification of more than 103,000 “enhancers” or sequences of DNA that can boost the expression and suppression of genes.
Ren said the work creates a new information resource for biomedical research, not just for better understanding of early human development, but also of the many diseases that trace their roots to our own.