Multigenerational epigenetic adaptation of the hepatic wound-healing response

Zeybel, Müjdat; Hardy, Timothy; Wong, Yi K; Mathers, John C.; Fox, Colin; Gackowska, Agata; Oakley, Fiona; Burt, Alastair D.; Wilson, Caroline; Anstee, Quentin M.; Barter, M.J.; Masson, Steven; Elsharkawy, Ahmed M.; Mann, Derek A.; Mann, Jelena

doi:10.1038/nm.2893

Cited by 261 publications

(232 citation statements)

References 55 publications

(62 reference statements)

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“…Epigenetic factors might also be a mechanism through which environmental exposures exert a heritable effect on disease risk. Remodelling of DNA methylation at key fibrosis modifier genes underpinned protection against carbon tetrachloride (CCl 4 ) induced liver fibrosis in male offspring of male mice that were themselves subjected to CCl 4 mediated liver injury 104 . Remarkably, DNA methyl ation remodelling occurred in the same genes in patients with NASH with mild fibrosis and intriguing data sug gests that epigenetic signatures present on circulating cell free DNA could be a potential biomarker of this effect and, therefore, disease severity 104,105 .…”

Section: Risk Factors: Nature or Nurture?mentioning

confidence: 99%

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Younossi

Anstee

Marietti³

et al. 2017

Nat Rev Gastroenterol Hepatol

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4,154

3,198

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Section: Risk Factors: Nature or Nurture?mentioning

confidence: 99%

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Younossi

Anstee

Marietti³

et al. 2017

Nat Rev Gastroenterol Hepatol

Self Cite

4,154

3,198

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“…ChIP assay was carried out as previously described [23] using 25 μg cross-linked chromatin prepared from EBV-BCL serum starved for 4 h before stimulation with 1 × 10 3 IU/mL IFN-α for 30 min. Antibodies used for IP (5 μg of each) were anti-STAT3 (C-20/sc-482; Santa Cruz) or normal rabbit IgG (PP64B; Millipore).…”

Section: Chip Assaymentioning

confidence: 99%

Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

et al. 2015

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Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/cMyc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies.Correspondence: Dr. Desa Lilic e-mail: desa.lilic@ncl.ac.uk * Both authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2834-2846 Immunity to infection 2835 Keywords: Chronic mucocutaneous candidiasis (CMC) HDAC inhibitors IL-17 STAT1 gain-of-function mutation STAT3 STAT1 inhibitorsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPatients with chronic mucocutaneous candidiasis (CMC) present with recurrent or persistent infections of the skin, nails, and mucosal membranes with the fungus Candida [1]. Candida is an opportunistic yeast that does not cause disease in healthy individuals despite inhabiting bodily surfaces as it is controlled by immune mechanisms, specifically Th-17 cells and cytokines produced by them [2]. Mucosal infections with Candida species indicate an underlying T-cell deficiency, which is most often secondary to immunosuppressive and/or chemotherapy, antibiotics, biological therapies, HIV, or other permissive circumstances. However, in rare patients, these infections present as a severe syndrome coined CMC, a primary immune deficiency in which the underlying cause is a genetic mutation affecting immune pathways essential for fungal protection [3]. Research in primary immune deficiency patients with isolated CMC has documented the crucial role of the signal transducer and activator of tra...

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“…On the one hand, there exist a large number of papers which find that environmental shocks lead to epigenetically induced phenotypic changes that become less pronounced from one generation to the next (Geoghegan, 2014, Schmitz et al, 2011, Remy, 2010. On the other hand, there exist several studies which suggest that epigenetic changes may skip the child generation or may predominantly manifest among the grandchildren of the affected individuals (Padmanabhan, 2013, Pembrey et al, 2006, Zeybel, 2012. 6 Therefore, epigenetics potentially has important implications for the effects of health interventions and the economic modeling of human capital formation.…”

Section: Epigenetic Imprintingmentioning

confidence: 99%

Transgenerational effects of childhood conditions on third generation health and education outcomes

Berg

Pinger

2016

Economics & Human Biology

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Phone: +49-621-181-1923; Fax: +49-228-73-9239. AbstractThis paper examines the extent to which pre-puberty nutritional conditions in one generation affect productivity-related outcomes in later generations. Recent findings from the biological literature suggest that the so-called slow growth period around age 9 is a sensitive period for male germ cell development. We build on this evidence and investigate whether undernutrition at those ages transmits to children and grandchildren. Our findings indicate that third generation males (females) tend to have higher mental health scores if their paternal grandfather (maternal grandmother) was exposed to a famine during the slow growth period. These effects appear to reflect biological responses to adaptive expectations about scarcity in the environment, and as such they can be seen as an economic correctional mechanism in evolution, with marked socio-economic implications for the offspring.

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Multigenerational epigenetic adaptation of the hepatic wound-healing response

Cited by 261 publications

References 55 publications

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

Transgenerational effects of childhood conditions on third generation health and education outcomes

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