Publications by authors named "Peter W S Hill"

6 Publications

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persisters undermine host immune defenses during antibiotic treatment.

Science 2018 12;362(6419):1156-1160

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK.

Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
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http://dx.doi.org/10.1126/science.aat7148DOI Listing
December 2018

Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte.

Nature 2018 03 7;555(7696):392-396. Epub 2018 Mar 7.

MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK.

Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5-E11.5, including genome-wide loss of 5-methylcytosine. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.
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http://dx.doi.org/10.1038/nature25964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856367PMC
March 2018

Dynamic changes in H1 subtype composition during epigenetic reprogramming.

J Cell Biol 2017 10 9;216(10):3017-3028. Epub 2017 Aug 9.

Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany

In mammals, histone H1 consists of a family of related proteins, including five replication-dependent (H1.1-H1.5) and two replication-independent (H1.10 and H1.0) subtypes, all expressed in somatic cells. To systematically study the expression and function of H1 subtypes, we generated knockin mouse lines in which endogenous H1 subtypes are tagged. We focused on key developmental periods when epigenetic reprogramming occurs: early mouse embryos and primordial germ cell development. We found that dynamic changes in H1 subtype expression and localization are tightly linked with chromatin remodeling and might be crucial for transitions in chromatin structure during reprogramming. Although all somatic H1 subtypes are present in the blastocyst, each stage of preimplantation development is characterized by a different combination of H1 subtypes. Similarly, the relative abundance of somatic H1 subtypes can distinguish male and female chromatin upon sex differentiation in developing germ cells. Overall, our data provide new insights into the chromatin changes underlying epigenetic reprogramming. We suggest that distinct H1 subtypes may mediate the extensive chromatin remodeling occurring during epigenetic reprogramming and that they may be key players in the acquisition of cellular totipotency and the establishment of specific cellular states.
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http://dx.doi.org/10.1083/jcb.201611012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626532PMC
October 2017

Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.

Mol Cell 2015 Nov 5;60(4):611-25. Epub 2015 Nov 5.

Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK. Electronic address:

The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.
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http://dx.doi.org/10.1016/j.molcel.2015.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672152PMC
November 2015

Reprogramming of cell fate: epigenetic memory and the erasure of memories past.

EMBO J 2015 May 27;34(10):1296-308. Epub 2015 Mar 27.

Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK

Cell identity is a reflection of a cell type-specific gene expression profile, and consequently, cell type-specific transcription factor networks are considered to be at the heart of a given cellular phenotype. Although generally stable, cell identity can be reprogrammed in vitro by forced changes to the transcriptional network, the most dramatic example of which was shown by the induction of pluripotency in somatic cells by the ectopic expression of defined transcription factors alone. Although changes to cell fate can be achieved in this way, the efficiency of such conversion remains very low, in large part due to specific chromatin signatures constituting an epigenetic barrier to the transcription factor-mediated reprogramming processes. Here we discuss the two-way relationship between transcription factor binding and chromatin structure during cell fate reprogramming. We additionally explore the potential roles and mechanisms by which histone variants, chromatin remodelling enzymes, and histone and DNA modifications contribute to the stability of cell identity and/or provide a permissive environment for cell fate change during cellular reprogramming.
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http://dx.doi.org/10.15252/embj.201490649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491992PMC
May 2015

DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: an emerging complex story.

Genomics 2014 Nov 27;104(5):324-33. Epub 2014 Aug 27.

MRC Clinical Sciences Centre, Imperial College London, Faculty of Medicine, Du Cane Road, W12 0NN London, UK. Electronic address:

Epigenetic reprogramming involves processes that lead to the erasure of epigenetic information, reverting the chromatin template to a less differentiated state. Extensive epigenetic reprogramming occurs both naturally during mammalian development in the early embryo and the developing germ line, and artificially in various in vitro reprogramming systems. Global DNA demethylation appears to be a shared attribute of reprogramming events, and understanding DNA methylation dynamics is thus of considerable interest. Recently, the Tet enzymes, which catalyse the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, have emerged as potential drivers of epigenetic reprogramming. Although some of the recent studies point towards the direct role of Tet proteins in the removal of DNA methylation, the accumulating evidence suggests that the processes underlying DNA methylation dynamics might be more complex. Here, we review the current evidence, highlighting the agreements and the discrepancies between the suggested models and the experimental evidence.
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http://dx.doi.org/10.1016/j.ygeno.2014.08.012DOI Listing
November 2014