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Chinese Scientists Find Key Transcription Factor (Oct-4) Activating Genome Expression in Human Embryos; Ancient Genes Are Expressed First; Transposons Very Active in Early Embryos

Chinese scientists have identified the crucial factor that activates gene expression in human embryos, bringing them one step closer to explaining the mystery of human development at a very early embryonic stage, according to a paper published in the March 22, 2018 issue of Cell. The article is titled “Chromatin Accessibility Landscape in Human Early Embryos and Its Association with Evolution.” Human life begins from a fertilized egg. However, in the first two days after fertilization, almost no genes are expressed in human embryos. Previously scientists did not know how genomes become active and start gene expression in early embryos. "What activates gene expression? The puzzle has been troubling scientists around the world for a long time. We were the first to find it," said Dr. Liu Jiang, senior author of the paper. During human growth, different genes must be expressed at the right time and right place. The genetic code stored in DNA is "interpreted" by gene expression, which gives rise to all the particular features of an individual. A team from Beijing Institute of Genomics, Chinese Academy of Sciences (CAS), led by Dr. Liu, together with a group from the Center for Reproductive Medicine, Shandong University, under Dr. Chen Zijiang, and a group from Guangzhou Medical University under Dr. Liu Jianqiao, found that Oct-4, a transcriptional factor, plays a crucial role in activating zygotic genome expression. In the first two days, a human zygote will grow into eight cells after three cell divisions. Once the embryo has eight cells, it will generate a sufficient amount of Oct-4, which will directly bind with DNA and switch on the gene expression, Dr. Liu said. The research also found that genome activation follows a particular sequence. "The older genes usually start expression at early embryonic stages, and younger ones at later stages," Dr. Liu said.

Humans have more than 20,000 genes, a reflection of a long chain of evolution. Some genes originated at the beginning of life on Earth, and are thus very old genes. Some originated in mammals, and are young ones. Some originated only in humans, and are deemed the youngest.

"We found that the expression of older genes usually occurs at earlier embryonic stages, as these genes, shared by more life species, are needed during earlier development," Dr. Liu said.

But how the human genome differentiates between old and young genes is still unclear and needs further study.

The study also found that transposons, a class of DNA elements, are very active in early human embryos, which might be a trigger of evolution.

"These transposons can jump from one position to another in a genome, and introduce DNA mutations. Because they are only active in early embryos, but not in differentiated tissues, the mutations caused by their mobility are more likely to be passed to the germ line, and then to the next generations," Dr. Liu said.
"As DNA mutations drive evolution, we believe that these active transposons have a big impact on human evolution," he said.

Before this study, the major hurdle in this research was the limited number of human embryos for experiment. Similar research would normally consume millions of animal embryos, but acquiring so many human embryos was neither possible nor ethical.

"We optimized the experiment methods so that the research could perform the assay with a very small number of human embryos," Dr. Liu said.
According to the paper, the scientists used just 50 to 100 cells, all derived from in vitro fertilization with written consent from donor couples.

[Press release] [Cell abstract]