Discovery of the key regulator of stem cell growth
In this present work, biologists at KAIST have found a breakthrough with respect to stem cell growth. Based on an understanding of LIN28B, researchers decided to test the possibility of LIN28A being post-translationally modified (e.g., acetylation, methylation or phosphorylation, ubiquitination). LIN28, one of the four iPS factors, is known to regulate let-7 microRNA (miRNA) to promote cell growth and the expression of MYC, a protein known to be over-expressed in cancer cells. Importantly it was found that LIN28A is methylated by SET7/9, and the methylated form of LIN28A is highly enriched in the nucleus. The methylated LIN28A blocks the maturation of pri-Let-7 miRNA; the methylation guides LIN28A to a putative localization region in the nucleolus.
Our body is comprised of six trillion cells. Trillion! It always amazes us that such an intangible number of cells derives from just one initial cell, the fertilized egg. After five intensive weeks of tireless cell divisions, the fertilized egg develops into an embryo, a state when it has the ability to be differentiated into any type of cell. For this reason, we call it ‘stem cell’ tissue.
Embryonic stem cells (ESC) were thought to be the only stem cell type until 2006, when Yamanaka from Kyoto University discovered that adult somatic cells can, too, acquire pluripotency by expressing just four genes (Oct3/4, Sox2, c-Myc, Klf4), namely iPS cells.
During the same year, Thomson (U. Wisconsin) also successfully induced pluripotency by expressing four retrovirus genes (Oct4, Sox2, Nanog and Lin28) from somatic cells.
This concept of de-differentiation, where fully differentiated cells rewind the molecular clock to regain the ability to differentiate to other types of cells, brought a ground-breaking shift in the paradigm of differentiation and opened a new field of research on ‘de-differentiation’.
LIN28, one of the four iPS factors, was first discovered in C.elegans and is known to regulate let-7 microRNA (miRNdlA) to promote cell growth and the expression of MYC, a protein known to be over-expressed in cancer cells.
In human, LIN28 exists as two paralogs: LIN28A in embryonic stem cells and LIN28B in adult somatic cells. Previously, LIN28A was known to be acting in cytoplasm to degrade let-7 miRNA and thereby promote MYC expression. On the other hand, the existence of LIN28A in the nucleus was thought to be marginal, and hence the role in the nucleus was questionable.
Interestingly, LIN28B, the paralog, solely acts only in the nucleus.
The researchers were extremely curious to determine whether LIN28A really has a function in the nucleus; after all, it shares many features with LIN28B. Since, post-translational modification such as acetylation, methylation or phosphorylation and ubiquitination can affect protein function, the researchers decided to test the possibility of LIN28A being post-translationally modified.
This guess prevailed: it was found that LIN28A is methylated by SET7/9, and the methylated form of LIN28A is highly enriched in the nucleus. The methylated LIN28A blocks the maturation of pri-Let-7 miRNA and the methylation guides LIN28A to a putative localization region in the nucleolus. Biochemical analysis revealed the underlying molecular mechanism that methylated form of LIN28A, compared to that of unmethylated, binds to pri-let-7 miRNA preferentially 4th line from bottom: stem cell, and therefore blocks the maturation of the pri-let-7 miRNA.
Furthermore, it was found that the methylation of LIN28A is critical in the maintenance of human embryonic stem cells (hESC). The researchers observed the genome-wide expression change of MYC-pathway genes when LIN28A or the LIN28A methyltransferase SET7/9 is silenced by siRNA.
These findings will help in the understanding of regulation of pluripotency in hESC cells and are expected to have numerous applications in the realm of stem cell treatment and cancer research.
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