8 results found
Hill P, Helaine S, 2019, Antibiotic Persisters and Relapsing Salmonella enterica Infections., Persister Cells and Infectious Disease, Editors: Lewis, Publisher: Springer Nature, ISBN: 9783030252410
Antibiotic persistence is defined as the ability of a subpopulation of bacteria within a clonal antibiotic-susceptible population to survive antibiotic treatment. Studies on antibiotic persistence have traditionally been carried out on bacteria cultured in laboratory media. However, over recent years, there has been a push to study antibiotic persisters in more physiologically relevant systems. Thus, the concept of antibiotic persistence during infection, which refers to the ability of a subpopulation of bacteria to survive combined host and antibiotic challenges, has emerged as a major new frontier of research. Here, we discuss the relevance and principles of this concept using relapsing Salmonella enterica infections as an example. We critically evaluate the clinical and experimental evidence for the existence and importance of antibiotic persisters in relapsing Salmonella infections; we outline our current understanding of the molecular mechanisms that enable successful antibiotic persistence during infection; and, finally, we discuss the challenges for this nascent field going forward.
Stapels DAC, Hill PWS, Westermann AJ, et al., 2018, Salmonella persisters undermine host immune defenses during antibiotic treatment, Science, Vol: 362, Pages: 1156-1160, ISSN: 0036-8075
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 Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella 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.
Hill PWS, Leitch HG, Requena CE, et al., 2018, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte, Nature, Vol: 555, Pages: 392-396, ISSN: 0028-0836
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)1. Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. 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.
Hajkova P, Schneider R, 2017, Dynamic changes in H1 subtype composition during epigenetic reprogramming, Journal of Cell Biology, Vol: 216, Pages: 3017-3028, ISSN: 1540-8140
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.
Amouroux R, Nashun B, Shirane K, et al., 2016, De novo DNA methylation drives 5hmC accumulation in mouse zygotes., Nature Cell Biology, Vol: 18, Pages: 225-233, ISSN: 1476-4679
Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs ,,,). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS-based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation.
Hajkova P, Nashun B, Hill PWS, et al., 2015, Continuous histone replacement by Hira is essential for normal transcriptional regulation and efficient de novo DNA methylation during mouse oogenesis, Molecular Cell, Vol: 60, Pages: 611-625, ISSN: 1097-4164
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.
Nashun B, Hill PW, Hajkova P, 2015, Reprogramming of cell fate: epigenetic memory and the erasure of memories past., EMBO Journal, Vol: 34, Pages: 1296-1308, ISSN: 0261-4189
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.
Hill PS, Amouroux R, Hajkova P, 2014, DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: An emerging complex story, GENOMICS, Vol: 104, Pages: 324-333, ISSN: 0888-7543
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