How to Make Stem Cells Nuclear Reprogramming Moves a Step Forward
The idea of taking a mature cell and removing its identity (nuclear reprogramming) so that it can then become any kind of cell, holds great promise for repairing damaged tissue or replacing bone marrow after chemotherapy
Hot on the heels of his recent Nobel prize Dr John B. Gurdon has published today in BioMed Central's open access journal Epigenetics & Chromatin research showing that histone H3.3 deposited by the histone-interacting protein HIRA is a key step in reverting nuclei to a pluripotent type, capable of being any one of many cell types.
All of an individual's cells have the same DNA,
yet these cells become programmed,
as the organism matures, into different
types such as heart, or lung or brain.
To achieve this different genes are more or less
permanently switched off in each cell lineage.
As an embryo grows, after a certain number
of divisions, it is no longer possible for cells
which have gone down the pathway to become
something else. For example heart cells cannot
be converted into lung tissue, and muscle cells
cannot form bone.
One way to reprogram DNA is to transfer the nucleus
of a mature cell into an unfertilized egg.
Proteins and other factors inside the egg
alter the DNA switching some genes on and other off
until it resembles the DNA of a pluripotent cell.
However there seem to be some difficulties with this
method in completely wiping the cell's 'memory'.
One of the mechanisms regulating the activation
of genes is chromatin and in particular histones.
DNA is wrapped around histones and alteration
in how the DNA is wound changes which genes
are available to the cell.
In order to understand how nuclear reprogramming works Dr Gurdon's team transplanted a mouse nucleus into a frog oocyte (Xenopus laevis). They added fluorescently tagged histones by microinjection, so that they could see where in the cell and nucleus the these histones collected.
Prof Gurdon explained, "Using real-time microscopy it became apparent that from 10 hours onwards H3.3 (the histone involved with active genes) expressed in the oocyte became incorporated into the transplanted nucleus. When we looked in detail at the gene Oct4, which is known to be involved in making cells pluripotent, we found that H3.3 was incorporated into Oct4, and that this coincided with the onset of transcription from the gene." Prof Gurdon's team also found that Hira, a protein required to incorporate H3.3 into chromatin, was also required for nuclear reprogramming.
"Manipulating the H3.3 pathway
may provide a way to completely
wipe a cell's 'memory' and produce
a truly pluripotent cell.
Half a century after showing that cells can be
reprogrammed this research provides a link
to the work of Shinya Yamanaka
(who shared the Nobel prize),
and suggests that chromatin is a
sticking point preventing artificially
induced reprogramming being
used routinely in the clinic."
Dr Steven Henikoff
Fred Hutchinson Cancer Research Center
1. HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes jerome jullien, carolina astrand, emmanuelle szenker, nigel garrett, genevieve almouzni and john gurdon Epigenetics & Chromatin (in press)
Chromatin roadblocks to reprogramming 50 years on
Peter J Skene and Steven Henikoff
BMC Biology (in press)
Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central's open access policy.
2. Epigenetics & Chromatin is a peer-reviewed, open access, online journal, which publishes articles that provide novel insights into epigenetic inheritance and chromatin-based interactions. @EpigenChromatin
3. BioMed Central (http://www.biomedcentral.com/) is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector. @BioMedCentral
Original article: http://www.eurekalert.org/pub_releases/2012-10/bc-ht102612.php