Torres-Padilla Lab
Epigenetics and Cell-Fate in Early Mammalian Development
About our Research
We combine high-resolution microscopy with single-cell genomics to study the epigenetic principles underlying cellular reprogramming in the mouse embryo.
In mammals, epigenetic reprogramming, the acquisition and loss of totipotency, and the first cell fate decision all occur within a three-day window after fertilization of the oocyte by the sperm. Molecularly, these processes are poorly understood, yet this knowledge is an essential prerequisite to uncovering principles of stem cells, chromatin biology, and thus regenerative medicine.
The chromatin in stem cells and in cells of the early embryo displays unique features compared to the chromatin of differentiated cells, including the lack of ‘conventional’ heterochromatin. We propose that the transition from a totipotent state to a differentiated one is regulated by dramatic changes in chromatin states and chromatin organisation, in particular the formation of new heterochromatin.
We study the molecular players and the sequence of events that lead to the establishment of heterochromatin de novo in the embryo. We use the repetitive elements in the mouse genome, in particular retrotransposons and the major satellite repeats found in the pericentromeric chromatin, as a model for these studies. This research has direct implications for epigenetic reprogramming and for our understanding of how a more compact chromatin configuration progressively restricts cell fate determination and cellular plasticity.
Following fertilisation, the gametes undergo epigenetic reprogramming in order to revert to a totipotent state. The mechanism through which embryonic cells subsequently acquire their fate and the role of chromatin dynamics in this process are largely unknown.
The one-cell embryo – the zygote - undergoes a series of cell divisions resulting in the formation of the blastocyst. By this time point, the first differentiation event in the mammalian embryo has occurred; segregating the outer trophectoderm, which is developmentally restricted to extra-embryonic tissues, from the inner cell mass, which comprises the first pluripotent embryonic cells. We use a variety of approaches, including single cell approaches, to determine i) the chromatin components, ii) their dynamic changes, and iii) their role in the formation of the two first lineages of the mammalian embryo. In addition, we use the data generated to model quantitative changes underlying cell fate determination. This research will have an impact on our understanding of stem cell biology and cellular plasticity.
Totipotent cells are unique to the early embryo and are characterised by an extraordinary potential to form the extra-embryonic tissues as well as the embryo proper. Thus, totipotent cells display larger plasticity than pluripotent cells. Histone modifications and DNA methylation patterns are dramatically remodelled during early development.
Nuclear architecture has recently emerged as a key epigenetic factor, but a role for nuclear architecture in regulating reprogramming and totipotency during early development has not been established. We are interested in understanding how the genome organisation within the nucleus is shaped during the transitions from totipotency to pluripotency, and in determining whether this organisation has a functional impact on driving cellular plasticity and cell fate. Uncovering the molecular features that establish and maintain totipotency will have major implications for our ability to manipulate cell fate and cellular state. We anticipate that this knowledge will open up the road to establishing more efficient protocols for cellular reprogramming in regenerative medicine.
The Torres-Padilla Lab
Recent Lab Publications
Iturbide Martinez De Albeniz, A. ; Ruiz Tejada Segura, M.L. ; Noll, C. ; Schorpp, K.K. ; Rothenaigner, I. ; Ruiz-Morales, E.R. ; Lubatti, G. ; Agami, A. ; Hadian, K. ; Scialdone, A. ; Torres-Padilla, M.E.
Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.Fukagawa, T. ; Torres-Padilla, M.E.
Exploring the cell nucleus: From chromosome structure to single-cell omics.Hains, A.E. ; Marques, J.G. ; Chetal, K. ; Nakatani, T. ; Ettinger, A. ; Biagi, C.A.O.d. ; Gonzalez‐Sandoval, A. ; Pillai, R. ; Gatto, A. ; Torres-Padilla, M.E. ; Sadreyev, R.I. ; Filbin, M.G. ; Rechem, C.V.
Abstract SY23-01: Diffuse midline gliomas: From cell cycle to therapeutic opportunities.Burton, A. ; Torres-Padilla, M.E.
Epigenome dynamics in early mammalian embryogenesis.Nakatani, T. ; Schauer, T. ; Pal, M. ; Ettinger, A. ; Altamirano-Pacheco, L. ; Zorn, J. ; Gilbert, D.M. ; Torres-Padilla, M.E.
RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.Pal, M. ; Schauer, T. ; Burton, A. ; Nakatani, T. ; Pecori, F. ; Hernández-Giménez, A. ; Nadelson, I. ; Marti-Renom, M.A. ; Torres-Padilla, M.E.
The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.Götz, M. ; Torres-Padilla, M.E.
Stem cells as role models for reprogramming and repair.Oomen, M.E. ; Rodriguez-Terrones, D. ; Kurome, M. ; Zakhartchenko, V. ; Mottes, L. ; Simmet, K. ; Noll, C. ; Nakatani, T. ; Mourra-Díaz, D.M. ; Aksoy, I. ; Savatier, P. ; Goke, J. ; Wolf, E. ; Kaessmann, H. ; Torres-Padilla, M.E.
An atlas of transcription initiation reveals regulatory principles of gene and transposable element expression in early mammalian development.Hermant, C. ; Mourra-Díaz, D.M. ; Oomen, M.E. ; Altamirano-Pacheco, L. ; Pal, M. ; Nakatani, T. ; Torres-Padilla, M.E.
The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation.Hains, A.E. ; Chetal, K. ; Nakatani, T. ; Marques, J.G. ; Ettinger, A. ; Junior, C.A.O.B. ; Gonzalez-Sandoval, A. ; Pillai, R. ; Filbin, M.G. ; Torres-Padilla, M.E. ; Sadreyev, R.I. ; Van Rechem, C.
Multi-omics approaches reveal that diffuse midline gliomas present altered DNA replication and are susceptible to replication stress therapy.Arner, A. ; Ettinger, A. ; Blaser, B.W. ; Schmid, B. ; Jeremias, I. ; Rostam, N. ; Binder-Blaser, V.
In vivo monitoring of leukemia-niche interactions in a zebrafish xenograft model.Ebisuya, M. ; Rayon, T. ; Diaz-Cuadros, M. ; Chalut, K.J. ; Wu, G. ; Dodd, A.N. ; Torres-Padilla, M.E. ; Levine, M.E. ; Gladyshev, V.N.
Understanding how cells and organisms keep time during development.Liu, B. ; He, Y. ; Wu, X. ; Lin, Z. ; Ma, J. ; Qiu, Y. ; Xiang, Y. ; Kong, F. ; Lai, F. ; Pal, M. ; Wang, P. ; Ming, J. ; Zhang, B. ; Wang, Q. ; Wu, J. ; Xia, W. ; Shen, W. ; Na, J. ; Torres-Padilla, M.E. ; Li, J. ; Xie, W.
Mapping putative enhancers in mouse oocytes and early embryos reveals TCF3/12 as key folliculogenesis regulators.Chen, Y.-L. ; Jones, A. ; Crawford, A. ; Sattler, M. ; Ettinger, A. ; Torres-Padilla, M.E.
Determinants of minor satellite RNA function in chromosome segregation in mouse embryonic stem cells.Oomen, M.E. ; Torres-Padilla, M.E.
Jump-starting life: balancing transposable element co-option and genome integrity in the developing mammalian embryo.Nakatani, T. ; Schauer, T. ; Altamirano-Pacheco, L. ; Klein, K.N. ; Ettinger, A. ; Pal, M. ; Gilbert, D.M. ; Torres-Padilla, M.E.
Emergence of replication timing during early mammalian development.Pal, M. ; Altamirano-Pacheco, L. ; Schauer, T. ; Torres-Padilla, M.E.
Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity.Lalonde, M. ; Ummethum, H. ; Trauner, M. ; Ettinger, A. ; Hamperl, S.
An automated image analysis pipeline to quantify the coordination and overlap of transcription and replication activity in mammalian genomes.Cossec, J.C. ; Traboulsi, T. ; Sart, S. ; Loe-Mie, Y. ; Guthmann, M. ; Hendriks, I.A. ; Theurillat, I. ; Nielsen, M.L. ; Torres-Padilla, M.E. ; Baroud, C.N. ; Dejean, A.
Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures.Bell, O. ; Burton, A. ; Dean, C. ; Gasser, S.M. ; Torres-Padilla, M.E.
Heterochromatin definition and function.Pecori, F. ; Torres-Padilla, M.E.
Dynamics of nuclear architecture during early embryonic development and lessons from liveimaging.Guthmann, M. ; Qian, C. ; Gialdini, I. ; Nakatani, T. ; Ettinger, A. ; Schauer, T. ; Kukhtevich, I. ; Schneider, R. ; Lamb, D.C. ; Burton, A. ; Torres-Padilla, M.E.
A change in biophysical properties accompanies heterochromatin formation in mouse embryos.Lubatti, G. ; Stock, M. ; Iturbide Martinez De Albeniz, A. ; Ruiz Tejada Segura, M.L. ; Riepl, M. ; Tyser, R.C.V. ; Danese, A. ; Colomé-Tatché, M. ; Theis, F.J. ; Srinivas, S. ; Torres-Padilla, M.E. ; Scialdone, A.
CIARA: A cluster-independent algorithm for identifying markers of rare cell types from single-cell sequencing data.Canat, A. ; Atilla, D. ; Torres-Padilla, M.E.
Hyperosmotic stress induces 2-cell-like cells through ROS and ATR signaling.Nakatani, T. ; Torres-Padilla, M.E.
Regulation of mammalian totipotency: A molecular perspective from in vivo and in vitro studies.
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