[R01] Epigenetic and metabolic mechanisms of environmentally-induced transgenerational germline dysfunction
Ente: National Institute on Alcohol Abuse and Alcoholism
Scadenza: 2028-04-30
Importo max: 344.429 EUR
Paese: US
Descrizione
PROJECT SUMMARY
The overarching goal of the research presented in this application is to dissect the genetic, epigenetic, and
metabolic programs that encode and transmit a memory of environmental exposure for several generations. In
that context, we aim to understand how environmental influences alter the reproductive program of organisms
in a transgenerational fashion and what makes the germline a particularly important and sensitive target of
exposures.
In mammals, in utero ethanol exposure is associated with an array of well-characterized morphological,
neurobehavioral, and reproductive issues. However, there is mounting evidence in a variety of model
organisms that some adverse reproductive and neurological features are also detectable in the third generation
following exposure indicating a transgenerational effect. Alcohol also has a clear epigenetic impact and directly
contributes to the modification of the epigenome. Nevertheless, despite the fact that heritable effects of alcohol
imply an alteration of the information contained in germ cells, it is unclear how the memory of ethanol exposure
is initiated in the germline and then transmitted to future generations. Here, we combine the tractability and
conservation of the model system C. elegans with state-of-the-art epigenomic analyses, classical genetic, and
cytological approaches to shed light on the mechanisms of memory of ethanol exposure. Our preliminary data
shows that ethanol exposure causes strong transgenerational reproductive and behavioral impairments. We
also show that, in line with recent mammalian studies, ethanol causes an increase in histone acetylation.
Thus, we hypothesize that ethanol exposure causes transgenerational perturbations of germline
function by altering the germline epigenome, specifically histone acetylation. Our aims are designed to
address the molecular, metabolic and epigenetic requirements for these transgenerational impacts of ethanol.
In aim 1, we will build on our preliminary reproduction data to interrogate through classical genetics tools
meiotic pathways at the root of ethanol's trans-generational increase in germline apoptosis and embryonic
lethality. In aim 2, we will examine via mass spectrometry the modulation in 80 different histone marks
stemming from direct ethanol exposure and test whether increased histone acetylation is a required event for
the initiation ethanol's transgenerational reproductive effects. Finally, in aim 3, we will test the epigenetic
requirement for the transgenerational transmission of ethanol's effects and also map by CUT&RUN the
changes in the epigenetic landscape of histone modifications in the germline.
At the completion of the aims, we will have identified the molecular underpinnings for the initiation and
transmission of ethanol transgenerational reproductive outcomes.
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: Patrick Allard
Progetto: 5R01AA030160-04
Settori: National Institute on Alcohol Abuse and Alcoholism
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