Stem Cell Precursors Revealed

Scientists in Brazil are contributing to cutting-edge research into stem cell developmental biology by the prestigious Gurdon Institute at the UK’s University of Cambridge.

A new study explains the way that enzymes can modify histones – the main proteins in a cell nucleus – very soon after a mammalian embryo is fertilized. This in turn determines the way all embryonic tissues will develop, and explains the functioning of “pluripotent cells,” which are the precursors of stem cells.

The study, entitled Citrullination regulates pluripotency and histone H1 binding to chromatin, was published January 26th in the online edition of the journal Nature.

The main authors of the article were Prof. Sir John Gurdon, recipient of the 2012 Nobel Prize for Physiology or Medicine, and Prof. Tony Kouzarides, recipient of the Heinrich Wieland Prize 2013.

Prof. Sir John Gurdon of Cambridge University

Prof. Sir John Gurdon of Cambridge University

A significant co-author was Clara Slade Oliveira, a Brazilian doctor of veterinary medicine from the State University of São Paulo (Unesp), and a researcher with the Brazilian Agricultural Research Corporation (Embrapa) at its Santa Mônica Experimental Field Animal Reproduction Laboratory in Valença, Rio de Janeiro. Her work is funded by the São Paulo Research  Foundation (FAPESP).

She observed this enzymatic activity during her doctoral work conducted on the Unesp campus in Jaboticabal (SP) under the guidance of Prof. Joaquim Mansano Garcia. She conducted a more specific study regarding the role of PADI4 (see below) during her post-doc research at the University of Cambridge with Prof. Magdalena Zernicka-Goetz, a Gurdon Institute Fellow and another co-author of the Nature article.

According to Dr Oliveira “the study whose findings were published in the Nature article dealt with the activation of certain enzymes that modify histones [the main proteins that make up the cell nucleus] in the initial phase of embryonic development, that is, before implantation of the embryo in the mother’s uterus.”

Part of the work done at the Gurdon Institute by Prof. Magdalena Zernicka-Goetz involves the mouse embryo. This provides an excellent model for studying mammalian development, including our own. It is also an excellent model to discover how to guide the differentiation of pluripotent cells towards specialised cell types. Initially mouse embryo cells are pluripotent and able to make any cell in the foetus or placenta but gradually this ability becomes restricted.

Blastocyst

Mouse embryo studies at Gurdon Institute

During this period, explained Dr Oliveira, “the zygote, which is the structure formed through fertilization of the ovum by a sperm cell, develops into a blastocyst, initially a structure that has fewer than 100 cells and is characterized by the presence of two distinct cell lineages.”

The main enzyme in question, peptidylarginine deiminase 4 (PADI4), appears to play an essential role in regulating the process of cell differentiation. During the initial stages of embryonic development, cells can give rise to any tissue in the body and placenta.

Once the blastocyst forms, there is a clear separation into two groups of cells: the inner cell mass (pluripotent) that gives rise to the embryo and the trophectoderm that forms the embryonic placenta. After this differentiation, the trophectoderm cells no longer take part in forming adult tissues. PADI4 contributes to the formation of the pluripotent compartment.

For the meantime this is pure research. However the Gurdon Institute works with epigenetics and cancer, so one possible future application of the study could result in obtaining new resources to inhibit the proliferation of tumour cells.

You can read a full article on the subject by Brazilian journalist José Tadeu Arantes by clicking here.

You can review the work of the Gurdon Institute and Prof. Magdalena Zernicka-Goetz’s work by clicking here.

The article Citrullination regulates pluripotency and histone H1 binding to chromatin (doi:10.1038/nature12942) is available to subscribers of Nature online at www.nature.com/nature/journal/vaop/ncurrent/full/nature12942.html.

For non-subscribers a short summary is visible by clicking here.

Blastocyst

Blastocyst

 

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