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Delayed self-regulation and time-dependent chemical drive leads to novel states in epigenetic landscapes

- Mitra, Mitra, Taylor, Paul, Hutchison, Chris, McLeish, T. C. B., Chakrabarti, Buddapriya

  • Authors: Mitra, Mitra , Taylor, Paul , Hutchison, Chris , McLeish, T. C. B. , Chakrabarti, Buddapriya
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Journal of the Royal Society Interface Vol. 11, no. 100 (2014), p.
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  • Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We show that the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
  • Description: The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far.We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit.We showthat the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells.We also comment on howsuch an oscillatory state can provide a framework for understanding more general feedback circuits in cell development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage

- Gibbs-Seymour, Ian, Markiewicz, Ewa, Bekker-Jensen, Simon, Mailand, Niels, Hutchison, Chris

  • Authors: Gibbs-Seymour, Ian , Markiewicz, Ewa , Bekker-Jensen, Simon , Mailand, Niels , Hutchison, Chris
  • Date: 2015
  • Type: Text , Journal article
  • Relation: Aging Cell Vol. 14, no. 2 (2015), p. 162-169
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  • Description: Lamins A/C have been implicated in DNA damage response pathways. We show that the DNA repair protein 53BP1 is a lamin A/C binding protein. In undamaged human dermal fibroblasts (HDF), 53BP1 is a nucleoskeleton protein. 53BP1 binds to lamins A/C via its Tudor domain, and this is abrogated by DNA damage. Lamins A/C regulate 53BP1 levels and consequently lamin A/C-null HDF display a 53BP1 null-like phenotype. Our data favour a model in which lamins A/C maintain a nucleoplasmic pool of 53BP1 in order to facilitate its rapid recruitment to sites of DNA damage and could explain why an absence of lamin A/C accelerates aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

B-type lamins in health and disease

- Hutchison, Chris

  • Authors: Hutchison, Chris
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Seminars in Cell and Developmental Biology Vol. 29, no. (2014), p. 158-163
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  • Description: For over two decades, B-type lamins were thought to have roles in fundamental processes including correct assembly of nuclear envelopes, DNA replication, transcription and cell survival. Recent studies have questioned these roles and have instead emphasised the role of these proteins in tissue building and tissue integrity, particularly in tissues devoid of A-type lamins. Other studies have suggested that the expression of B-type lamins in somatic cells influences the rate of entry into states of cellular senescence. In humans duplication of the LMNB1 gene (encoding lamin B1) causes an adult onset neurodegenerative disorder, termed autosomal dominant leukodystrophy, whilst very recently, LMNB1 has been implicated as a susceptibility gene in neural tube defects. This is consistent with studies in mice that reveal a critical role for B-type lamins in neuronal migration and brain development. In this review, I will consider how different model systems have contributed to our understanding of the functions of B-type lamins and which of those functions are critical for human health and disease. © 2014 The Author.

Do lamins influence disease progression in cancer?

- Hutchison, Chris

  • Authors: Hutchison, Chris
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Advances in Experimental Medicine and Biology Vol. 773, no. (2014), p. 593-604
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  • Description: For nearly 60 years, diagnosis of cancer has been based on pathological tests that look for enlargement and distortion of nuclear shape. Because of their involvement in supporting nuclear architecture, it has been postulated that the basis for nuclear shape changes during cancer progression is altered expression of nuclear lamins and in particular lamins A and C. However, studies on lamin expression patterns in a range of different cancers have generated equivocal and apparently contradictory results. This might have been anticipated since cancers are diverse and complex diseases. Moreover, whilst altered epigenetic control over gene expression is a feature of many cancers, this level of control cannot be considered in isolation. Here I have reviewed those studies relating to altered expression of lamins in cancers and argue that consideration of changes in the expression of individual lamins cannot be considered in isolation but only in the context of an understanding of their functions in transformed cells. © 2014 Springer Science+Business Media New York.
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