I obtained my undergraduate degree in veterinary medicine from the University of La Plata, Argentina in 1996 and this was followed by a PhD (Suma Cum Laude) from the University of Munich, Germany in 2001. My first postdoctoral training was done under supervision of Prof. Keith Campbell (2001-2003), and this was followed by a Marie Curie Fellowship (2002-2004). In 2005 I was awarded an RCUK Fellowship (2005-2010). In 2010 I became a Lecturer and in 2015 an Associate Professor in Developmental Epigenetics at the Division of Animal Sciences, School of Biosciences, UoN.
Biotechnology in Animal Physiology (D235z1; Module convenor)
Advanced Developmental Biology (C13595)
Regulation and Organisation in Animals (D212Z6)
Practical Animal Physiology (D223z6)
M.Med Sci in Assisted Reproductive Technology (A117)
Techniques in Developmental Biology (D24TDB)
Our laboratory investigates the developmental mechanisms involved in the generation of pluripotent cells. Our aim is to understand the molecular basis of pluripotency, and use the strategies employed… read more
Our laboratory investigates the developmental mechanisms involved in the generation of pluripotent cells. Our aim is to understand the molecular basis of pluripotency, and use the strategies employed by the embryo to recapitulate these events in laboratory conditions that will enable the manipulation of somatic cells.
The current main research areas in the lab include:
- Reprogramming somatic cells into a pluripotent state
- Germ cell development in mammals
- Stem cells from epiblast stage embryos
Reprogramming cells into a pluripotent state
In this project we investigate the mechanisms that underlie the reversal of cell fate. Changing the identity of a cell into another, or converting a cell into a pluripotent cell, can have multiple applications particularly for regenerative medicine, drug screening, and toxicological assays. This process, also known as cellular reprogramming, was first described following the transfer of a somatic cell into an enucleated oocyte. The oocyte has the remarkable capacity to remodel somatic chromatin and renders it pluripotent after a few cell divisions. We are uncovering the epigenetic mechanisms by which oocyte molecules remodel somatic chromatin. We have developed a system for studying somatic cell reprogramming which uses extracts from salamander (Ambystoma mexicanum) and frog (Xenopus laevis) oocytes. This system enables us to perform dynamic analysis of chromatin remodelling and identify biochemical activities responsible for these changes. Gene specific and genome-wide analysis of specific regions show multiple changes in somatic chromatin that are part of the reprogramming events initiated by oocyte molecules. These changes in chromatin associated proteins are correlated with reduction in DNA methylation of specific gene promoters. We are currently investigating the mechanisms involved in these remodeling events, as well as developing culture methods for the reprogrammed cells.
Germ cell development in mammals
Germ cells are responsible for passing the genetic information of the parents onto the next generation. The developmental program of these cells involves unique mechanisms that contribute to eliminate epimutations that may otherwise be passed on to the next generation. Much of the knowledge of how germ cells are first segregated from the pluripotent cells of the embryo, as well as how they are reprogrammed before becoming fully competent for fertilization is performed in mice, a conventional model organism. The specification of germ cells occurs very early during mouse development, which has led to speculations as to whether this mechanism has evolved to safeguard the correct establishment of the germline in rapidly developing species. The mechanism of germ cell specification has not been studied in detail in other species, and our laboratory is interested in elucidating these mechanisms in other mammals that share important developmental features. Larger mammals (humans, pigs, sheep and cows) have a much slower development, suggesting that the mechanisms for the establishment of different cell lineages, including the germline, may be under different control. An important difference between the embryos of mice and other mammalian species, is that mouse embryos develop as a conical structure, which implies that cellular movements are very characteristic for this type of embryo. Other mammals develop as a flat embryonic disc, which means that the cellular movements are completely different to rodents. There is some evidence indicating that cow and pigs embryos develop germ cells in the posterior part of the embryo, however, these cells arise late in development. In contrast to mice, these cells remain pluripotent and uncommitted until much later developmental stages. We are currently investigating the mechanisms that characterize the development of germ cells in embryos from large mammals such as pigs. Given that many aspects of early pig embryo development are similar to human embryos, we use these embryos to uncover fundamental mechanisms of germ line development with relevance to human. The findings from our in vivo characterization are validated with functional experiments using human ESC/iPS and pig EpiSC/iPS. We expect that this work will impact in our ability to develop efficient methods for generating human gametes in the laboratory.
Stem cells from epiblast stage embryos
A related aspect of our research into germ cell specification in large mammals is the fact that the bilaminar embryo begins gastrulation at a relatively late stage compared to rodent embryos. This provides an extended window of time for accessing uncommitted pluripotent cells from the epiblast. Epiblast cells are pluripotent cells that contribute to all tissues of the fetus, and recent work shows that these cells can be derived from rodent embryos. We have isolated pig epiblast stem cells and our characterization shows that these cells share signaling mechanisms similar to rodent epiblast cells. The cells can be propagated in vitro for a large number of passages, and importantly, pig stem cell share numerous markers with human embryonic stem cells. Establishing pig embryonic stem cells will serve as a valuable model for gene targeting and for the generation of animal models of human disease. There are large numbers of human diseases that can be modeled in pigs, due to similar physiological processes. Several genetic disorders leading to cardiovascular diseases, neural disorders, obesity, retinitis and cancers (colon in particular) are among the most relevant models than can be generated to study the physiopatology, diagnosis and therapeutics of such disorders. We are studying the features of stemness in these cells. The work on the cells together with our study of equivalent stages from embryos produced in vivo will allow us to establish the molecular events leading to the development of the trilaminar embryo.
BBSRC, Medical Research Council, European Union (Horizon 2020) and Zoetis.
Current Lab Members:
Dr. Sarah Withey (Research Fellow)
Dr. Priscila Ramos-Ibeas (Research Fellow)
Doris Klisch (Lab Manager)
Sidar Bereketoglu (PhD Student)
Choulia Mola (PhD student)
Fabio Amaral (PhD student funded by MRC)
Darren Crowley (PhD student)
Haitham Alhilfi (PhD student)
Judith Gomez-Martinez (PhD student)
Helen Anderton (PhD student)
Sebastian Lazar, MPhil (2008)
Xiaoni Sun, MRes (2010)
Alejandro Contreras, PhD (2011)
Somsin Petyim, PhD (2013)
Griselda Valdez Magana, PhD (2014)
Sergio German, PhD (2015)
Haixin Zhang, PhD (2016)