Let7 miRNAs, Lin-28, Cancer and Stem Cells

Last past week was incredible. A slew of very important papers stemming from basic science and having deep impacts on cancer and stem cells came out in Nature and Science. Both stories came from labs here at Harvard Medical School, and everyone's been talking about both papers. The first story is complicated - but I wanted to use it to give a history of one aspect of cancer research. I have already written a two part intro into the topic (here and here). The other story, which was presented at last week's New England RNA Data Club, is now available online, I'll sum up the incredible discovery below the fold.

This whole project was initiated by Srini Viswanathan a grad student in the Daley and Richard labs here at HMS. I heard that the whole project took three or four months from conception to manuscript.

Background: (For more on miRNAs click here.) miRNAs come in families. The members of each family are nearly identical to eachother and target similar transcripts for silencing and/or destruction.

When a miRNA is transcribed it is made at a long stem loop in the nucleus. An enzyme named Drosha cleaves the loose ends off of the stem loop. The shorter, half-processed miRNA is then exported to the cytoplasm where the loop is chopped off by Dicer. One strand is then loaded into the RISC complex and is used to inhibit translation and/or degrade an mRNA.

It had been noted by many researchers that the let7 family of miRNAs are inhibited in most cancer cell lines and in stem cells. It turns out that embryonic stem cells cells make plenty of let7 precursors that remain unprocessed. So what's the mechanism? It appears as if the stem loop of the let7 miRNAs aren't properly processed by Drosha. Knowing all this, Srini developed an assay to measure miRNA processing. He isolated a factor that inhibits Drosha from ES cell extracts that turned out to be a known protein called Lin-28. The curious part is that this protein only prevents the processing of the let7 family of miRNAs. We're not sure why this is.

Now why is this so amazing?

Remember all those papers on iPS (induce pluripotent stem) cells? Two years ago the Yamanaka group figured out that if you expressed 4 transcription factors in mouse skin cells, you can convert the cells into iPS cells. A year later the results were repeated in human cells. At the same time the Thomson group demonstrated that you could express a different set of proteins to get the same reprogramming event. Two of the Thomson factors were identical to the genes expressed by Yamanaka (Sox2 and Oct 3/4), one of the new genes encoded another transcription factor known to be important for stem cell generation (Nanog) and the last gene encoded an RNA binding protein named ... Lin-28.

Yes, you need to inhibit a specific family of miRNAs to reprogram your cells. Amazing.

Srinivas R. Viswanathan, George Q. Daley, and Richard I. Gregory
Selective Blockade of MicroRNA Processing by Lin-28
Published online February 21 2008; doi:10.1126/science.1154040 (Science Express)

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Nice to see some sanity at ScienceBlogs these days...I might be going over the paper some time soon, it sounds really interesting. It looks like it was posted ahead of print, but I can access it through my university's library.

Thank you very much for this clear and concise explanation -- I am learning a lot from this series.

Memo to ScienceBorg(TM) overlords: Get more bloggers like Alex.

By Neuro-conservative (not verified) on 24 Mar 2008 #permalink

Thanks Alex. This is really cool.

3-4 months?? They must either be incredibly lucky, or slogged their asses off. I suspect the latter.

interesting... I just did a class presentation this afternoon on miR373 and mir520c as promoters of metastasis (Nature Cell Biology, Jan 13 2008). Long story short, they mentioned that there is an inverse relationship between CD44 and miR373.... Someone in my class pointed out that CD44 is a breast cancer stem cell marker... I wonder if this is something that can be looked into further? I'm not making sense...

Anyway, just a random thought that has not much to do with your post. I'm just starting out as a PhD student in Cell biology after all... ;)

I have heard a very similar Let7 processing story at least one year ago from a graduate student in my department. His story was in the process of revision and got rejected immediately after the science paper was online......

By anonymous (not verified) on 07 Apr 2008 #permalink

That's funny, a couple of days ago I heard about the existence of another group with the same data but they got scooped. Must be the same folks. That really sucks.

yes. its called stealing.

By anonymous (not verified) on 19 Nov 2009 #permalink