Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance

Abstract Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.

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Trichloroethylene exposure alters dimethylated histone three lysine four in protein kinase A signaling pathway chromatin of rat sperm†

Biology of Reproduction ◽

10.1093/biolre/ioz155 ◽

2019 ◽

Vol 101 (5) ◽

pp. 875-877

Author(s):

Angela R Stermer ◽

Shelby K Wilson ◽

David Klein ◽

Susan J Hall ◽

Kim Boekelheide

Keyword(s):

Signaling Pathway ◽

Chromatin Immunoprecipitation ◽

Epigenetic Inheritance ◽

Transgenerational Inheritance ◽

Z Score ◽

Epididymal Sperm ◽

Transgenerational Epigenetic Inheritance ◽

Differential Region ◽

Generation Sequencing ◽

Kinase A

Abstract Histone three lysine four dimethylation (H3k4me2) in sperm is conserved across species and is linked to transgenerational epigenetic inheritance. To test whether H3K4me2 is a target for transgenerational inheritance of toxicity, a daily gavage bolus exposure of trichloroethylene (TCE) (1000 mg/kg/day) was given to rats for 14 weeks, then epididymal sperm were isolated and native chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) of H3K4me2 was performed. Differential region analysis determined there were 2608 significantly differential H3K4me2 regions after TCE exposure, 477 were significantly increased and 2131 were significantly decreased. Z-score enrichment of differential regions determined there were significantly decreased H3k4me2 in the coding and regulatory regions of genes in the PKA signaling pathway. These changes account for TCE induced spermatozoal toxicity and show H3K4me2 is a target for paternal inheritance of toxicity.

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How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Diabetes ◽

10.2337/db20-1734-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1734-P

Author(s):

AUSTIN REILLY ◽

SHIJUN YAN ◽

ALEXA J. LONCHARICH ◽

HONGXIA REN

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Dietary Fat ◽

Fat Intake ◽

Dietary Fat Intake ◽

Genetic Mouse Model

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Faculty Opinions recommendation of Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371068.14893062 ◽

2012 ◽

Author(s):

Ferdinando Boero

Keyword(s):

Caenorhabditis Elegans ◽

Epigenetic Inheritance ◽

Transgenerational Epigenetic Inheritance

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Faculty Opinions recommendation of RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737854462.793574751 ◽

2020 ◽

Author(s):

Laurent Villard

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Epileptic Encephalopathy ◽

Genetic Mouse Model

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Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽

10.3390/nu13041181 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1181

Author(s):

Raffaella Soleti ◽

Marine Coué ◽

Charlotte Trenteseaux ◽

Gregory Hilairet ◽

Lionel Fizanne ◽

...

Keyword(s):

Blood Pressure ◽

Mouse Model ◽

Aortic Root ◽

De Novo ◽

Body Weight Gain ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Hemodynamic Parameters ◽

Cellular Models ◽

Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

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Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis

Cancers ◽

10.3390/cancers13071515 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1515

Author(s):

Keiichiro Okuda ◽

Atsushi Umemura ◽

Shiori Umemura ◽

Seita Kataoka ◽

Hiroyoshi Taketani ◽

...

Keyword(s):

Mouse Model ◽

Glucocorticoid Receptor ◽

Nuclear Translocation ◽

Growth Factor Receptor ◽

Public Health Problem ◽

Egfr Signaling ◽

Alcoholic Steatohepatitis ◽

Genetic Mouse Model ◽

Treatment And Prevention ◽

Egfr Expression

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

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